ORCID Profile
0000-0001-8535-6003
Current Organisations
University of Cape Town
,
Royal Australasian College of Physicians
,
Melbourne Health
,
Australasian College of Dermatologists
,
University of Melbourne
,
University of Cape Town Department of Medicine
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 10-2018
DOI: 10.1111/IMJ.14059
Abstract: Hereditary haemorrhagic telangiectasia is characterised by abnormal blood vessel formation, producing telangiectasia and arteriovenous malformations in multiple organs. Information regarding possible renal involvement in hereditary haemorrhagic telangiectasia is limited. This study assessed renal structure and function in 11 patients with genetically confirmed diagnosis and known arteriovenous malformations in lung, liver, gastrointestinal tract or brain. All had significant current or past epistaxis. Despite the vascularity of the kidneys, we found no evidence of renal involvement. This observation warrants further consideration.
Publisher: Frontiers Media SA
Date: 05-2019
Publisher: Elsevier BV
Date: 09-2018
Publisher: Oxford University Press (OUP)
Date: 28-08-2012
DOI: 10.1093/JNCI/DJS351
Publisher: Springer Science and Business Media LLC
Date: 13-08-2014
Publisher: Springer Science and Business Media LLC
Date: 08-02-2018
Publisher: Springer Science and Business Media LLC
Date: 17-07-2007
DOI: 10.1007/S10689-007-9154-8
Abstract: The co-existence of mutations in the BRCA1 and BRCA2 genes is unusual, and to date almost all cases reported have had at least one of the Ashkenazi founder mutations. We report on a family in whom in iduals are double heterozygotes for a mutation in BRCA1 and a novel splice site mutation in BRCA2. The phenotypes are discordant, where one sister has had multiple cancers in the BRCA spectrum, while the other is unaffected at 65 years of age. The utility of testing is discussed, and the completion of diagnostic testing despite the finding of a potentially causal mutation is validated.
Publisher: Wiley
Date: 09-1985
DOI: 10.1111/J.1399-0004.1985.TB00393.X
Abstract: Sotos syndrome, or Cerebral Gigantism is recognised as the syndromic association of mental retardation, macrocephaly and prenatal onset of accelerated growth. A kindred has been investigated in which the father and 4 affected offspring all have the Sotos syndrome. Autosomal dominant inheritance has been postulated in the past, and the family conform to this genetic pattern.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2020
Publisher: Wiley
Date: 09-2017
DOI: 10.1111/IMJ.13528
Abstract: When registries collect accurate clinical data over time, they can act as fundamental support structures for patients and their families and powerful cost-effective instruments to support clinical trials and translational research to improve quality of care, quality of life and survival. Registries are critical for rare diseases (RD) with low prevalence and propensity for variation in treatment and outcomes. Rare Voices Australia is leading a call for action to the research and clinical community to prioritise RD data collection and develop an integrated RD Registry strategy for Australia. Financial, operational and governance challenges exist for establishing and maintaining RD registries. As a multidisciplinary team whose interests converge on RD, we highlight the need for the establishment of an Australian RD Registry Alliance. This 'umbrella' organisation will: (i) bring together existing RD registries across Australia (ii) establish National RD Registry Standards to support interoperability and cohesion across registries (iii) develop strategies to attract sustainable funding from government and other sources to maximise the utility of existing RD registries and support the development of new RD registries. The most important role for the Alliance would be to use the RD registries for translational research to address current knowledge gaps about RD and to improve the care for the over 1.4 million Australians estimated to live with RD.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.HLC.2018.07.017
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially life-threatening genetic cardiomyopathy with a spectrum of clinical presentations including sudden cardiac death (SCD). Clinical and genetic data of 44 probands referred to a cardiac genetics clinic (2007-2017) who met 2010 Task Force Criteria (TFC) for ARVC diagnosis were included. Thirty-three (33) (75%) male, 20 (45%) were referred by the Victorian Institute of Forensic Medicine. Presentation that lead to diagnosis included ARVC-related SCD (n=19), SCD due to alternate cause of death (n=1), aborted cardiac arrest (n=6), stable symptomatic ventricular tachycardia (n=14), palpitations (n=3) and presyncope (n=1). Left ventricular involvement (50%) was more common in the SCD subgroup (84% vs 21%, p<0.001). Genetic testing (n=39) revealed a pathogenic mutation in 16 (commonest: plakophillin-2 (n=9)), a variant of uncertain significance (VUS) in 15, with no abnormality in eight. In the SCD subgroup, median age at death was 44.7 years and 74% were male. Genetic testing (n=16) in this subgroup revealed a pathogenic mutation in six patients (commonest: desmoplakin (n=4)). Comparison of the two commonest mutations (PKP2 and desmoplakin [DSP]) showed DSP mutation was more frequently associated with SCD (p<0.01) and LV involvement (p<0.001). Screening of 117 relatives has lead to ARVC diagnosis in 29 patients. Arrhythmogenic right ventricular cardiomyopathy has a heterogeneous and often severe clinical presentation. Sudden cardiac death and aborted cardiac arrest (ACA) are common, demonstrating electrical abnormalities appear early in the ARVC phenotype. Left ventricular involvement was common and may reflect a worse prognosis. Genetic testing is essential in family screening and may be helpful in risk assessment. Desmoplakin mutation is associated with LV involvement and may be indicative of worse prognosis and increased risk of SCD. Genetic screening of proband family members in a specialised multidisciplinary clinic is essential in early diagnosis of affected family members.
Publisher: Springer Science and Business Media LLC
Date: 05-2017
DOI: 10.1038/S41525-017-0017-4
Abstract: Organisations and governments seeking to implement genomics into clinical practice face numerous challenges across multiple, erse aspects of the health care system. It is not sufficient to tackle any one aspect in isolation: to create a system that supports genomic medicine, they must be addressed simultaneously. The growing body of global knowledge can guide decision-making, but each jurisdiction or organisation needs a model for genomic (or personalised) medicine that is tailored to its unique context, its priorities and the funds available. Poor decisions could greatly reduce the benefits that could potentially arise from genomic medicine. Demonstration projects enable models to be tested, providing valuable evidence and experience for subsequent implementation. Here, we present the Melbourne Genomics Health Alliance demonstration project as an exemplar of a collaborative, holistic approach to phased implementation of genomics across multiple autonomous institutions. The approach and lessons learned may assist others in determining how best to integrate genomics into their healthcare system.
Publisher: AMPCo
Date: 08-2015
DOI: 10.5694/MJA15.00236
Publisher: Springer Science and Business Media LLC
Date: 28-02-2018
DOI: 10.1038/S41467-018-03058-6
Abstract: Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA s les provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2015
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1038/GIM.2017.185
Publisher: Oxford University Press (OUP)
Date: 22-09-2022
DOI: 10.1111/CED.14883
Abstract: In the clinical investigation of a family with debilitating centrofacial pruritus by exome sequencing, we have observed a clear segregation of the TRPM3 variant outlined, which is highly suggestive of a causal relationship.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2007
DOI: 10.1038/NATURE05887
Publisher: BMJ
Date: 07-05-2008
Publisher: Massachusetts Medical Society
Date: 23-06-2016
Publisher: Oxford University Press (OUP)
Date: 22-07-2021
DOI: 10.1111/BJD.20521
Publisher: Elsevier BV
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41416-020-01185-W
Abstract: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. For pregnanediol-3-glucuronide, there were no genome-wide significant associations for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10 –18 ) in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10 –8 ). The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Publisher: Wiley
Date: 09-1991
DOI: 10.1111/J.1749-6632.1991.TB19584.X
Abstract: Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafness-depigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type II (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This latter entity is apparently much less common in Southern Africa than in other parts of the world.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2019
DOI: 10.1186/S13053-019-0127-3
Abstract: We previously reported that in pathogenic mismatch repair ( path_MMR ) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1 , 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within 1.5, 1.5–2.5, 2.5–3.5 and at 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5–3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively ( p 0.001). Ten-year crude survival when the last colonoscopy had been 1.5, 1.5–2.5, 2.5–3.5 or 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively ( p = 0.91). In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2017
Publisher: Wiley
Date: 07-10-2019
DOI: 10.1111/AJD.12938
Publisher: The Endocrine Society
Date: 06-2013
DOI: 10.1210/JC.2013-1400
Abstract: Reports of the coexistence of pituitary adenomas and pheochromocytoma araganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors. Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation. A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years. An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele. This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1038/GIM.2013.44
Abstract: Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified. Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002-2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected. A total of 265 unrelated in iduals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012). Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.
Publisher: MDPI AG
Date: 10-10-2023
Publisher: Elsevier BV
Date: 11-2020
Publisher: Hindawi Limited
Date: 14-01-2014
DOI: 10.1111/ECC.12163
Abstract: Breast cancer and its treatment have complex ramifications for women of reproductive age, including reduced fertility. With the aim of increasing understanding of what it means to women to manage fertility and motherhood in the years after a diagnosis of breast cancer, in-depth qualitative interviews were conducted with 10 women aged 26-45 years, living in Victoria, Australia, who had been diagnosed with breast cancer aged 25-41. Transcripts were analysed thematically and interpreted within narrative theory. Six themes linking breast cancer to fertility and motherhood were identified: diagnosis as a pivotal life event, robbed of time and choice, significance of fertility, being a mother, narrative justification, and life after breast cancer treatment. Women without children described a preoccupying sorrow about lost fertility. Women's accounts yielded evidence of narrative meaning-making, including justifying their decisions and actions in relation to survival, treatment and fertility, and coping with adversity by developing consoling plots. Breast cancer, fertility and reproductive health are inter-linked in erse ways which have immediate and long-term consequences. Even if women are receiving optimum fertility management, it is evident that some women of reproductive age will need continuing post-cancer care to manage and ameliorate ramifications of diminished or lost fertility.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.HUMPATH.2014.06.020
Abstract: Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6% P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer-specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor.
Publisher: Informa UK Limited
Date: 2013
DOI: 10.1080/07399332.2012.735729
Abstract: Breast cancer and its treatment in reproductive-age women can reduce fertility and compromise family formation. To learn about women's experiences of fertility-related cancer care we interviewed 10 women (aged 26-45), at least one year postdiagnosis. Thematic analysis revealed that all women, including one who chose to be child-free, valued fertility and motherhood. They reported experiencing varied fertility-related care, from support for fertility preservation to apparent disregard of their fertility concerns. Women's needs were heterogeneous, but all wanted health care providers to communicate fertility options and avoid assumptions about women's fertility desires while working to extend each woman's life.
Publisher: BMJ
Date: 09-2020
Abstract: The CHEK2 gene is mostly considered as a moderate breast cancer gene with the result that many clinicians have a narrow focus. We present the 10-year journey of a man who had five different cancers and had iterative genetic testing including for Li-Fraumeni syndrome, eventually to discover a pathogenic variant in the CHEK2 gene, possibly explaining his numerous cancers. This diagnosis offered him closure which he had desperately sought for well over a decade. A pathogenic variant in the CHEK2 gene can potentially explain these cancers because of its function as a tumour suppressor gene. Consideration is warranted of what this means for in iduals with CHEK2 variants who may develop multiple cancers, their prognosis and whether different treatment modalities such as chemotherapy, radiotherapy or target agents would need modification. We encourage more research into the many faces of the CHEK2 gene and the potential for predisposition to multiple cancers.
Publisher: Wiley
Date: 08-08-2015
DOI: 10.1111/CODI.12940
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2005
Publisher: Springer Science and Business Media LLC
Date: 19-04-2016
Publisher: Wiley
Date: 07-2014
DOI: 10.1111/IMJ.12457
Abstract: The present study aims to describe the phenotypic features of patients with hereditary haemorrhagic telangiectasia (HHT) seen at Royal Melbourne Hospital, Victoria, Australia, and to customise a protocol for surveillance of patients with HHT. This is a retrospective study in a tertiary referral hospital of all patients referred to the Clinical Genetics Service between 2007 and 2011 with a suspected diagnosis of HHT. Data abstracted from patient clinical records were analysed for clinical features, types of HHT and genetic testing results where available. Our cohort comprising 40 females and 23 males patients was assessed using the Curacao criteria. Twenty-two patients fulfilled the criteria for a definite diagnosis, 30 had a possible diagnosis, and 11 patients were assessed as unlikely to have HHT at the time of data analysis. Seventeen patients had pulmonary arteriovenous malformations (AVM), five had cerebral AVM, five had hepatic AVM, three had confirmed bowel telangiectasia, and one patient had a pancreatic AVM. Two female patients with HHT had complicated pregnancies during their follow up with us. Three families had mutations in the endoglin (ENG gene), three had mutations in the ACVRL1 gene, and two families had mutations in the SMAD4 gene. HHT is a multisystemic disorder and needs involvement of a team with experience in managing patients with HHT.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.17.00143
Abstract: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC. Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58 interquartile range [IQR], 47-101 v 6 IQR, 4-10 P .001), as was the MSIsensor score (median, 25.1 IQR, 17.9-31.2 v 0.03 IQR, 0-0.44 P .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC. LS- and sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.
Publisher: Wiley
Date: 17-01-2014
DOI: 10.1111/AJD.12131
Publisher: Massachusetts Medical Society
Date: 03-03-2011
DOI: 10.1056/NEJMC1012357
Publisher: Oxford University Press (OUP)
Date: 22-05-2020
Abstract: Globular cluster progenitors may have been detected by Hubble Space Telescope, and are predicted to be observable with James Webb Space Telescope (JWST) and ground-based extremely large telescopes with adaptive optics. This has the potential to elucidate the issue of globular cluster formation and the origins of significantly helium-enriched subpopulations, a problem in Galactic astronomy with no satisfactory theoretical solution. Given this context, we use model stellar tracks and isochrones to investigate the predicted observational properties of helium-enriched stellar populations in globular cluster progenitors. We find that, relative to helium-normal populations, helium-enriched (ΔY = +0.12) stellar populations similar to those inferred in the most massive globular clusters, are expected, modulo some rapid fluctuations in the first ∼30 Myr, to be brighter and redder in the rest frame. At fixed age, stellar mass, and metallicity, a helium-enriched population is predicted to converge to being ∼0.40 mag brighter at $\\lambda \\approx 2.0\\, {\\mu \\rm m}$, and to be 0.30-mag redder in the JWST–NIRCam colour (F070W − F200W), and to actually be fainter for $\\lambda \\lesssim 0.50 \\, {\\mu \\rm m}$. Separately, we find that the time-integrated shift in ionizing radiation is a negligible $\\sim \\!5{{\\ \\rm per\\ cent}}$, though we show that the Lyman-α escape fraction could end up higher for helium-enriched stars.
Publisher: Wiley
Date: 30-07-2020
DOI: 10.1002/IJC.33214
Publisher: Wiley
Date: 15-07-2023
DOI: 10.1002/SKI2.140
Abstract: The Ehlers‐Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with features of skin hyperextensibility, joint hypermobility, abnormal scarring and fragility of skin, blood vessels and some organs. The disease is generally diagnosed through the cluster of clinical features, though the addition of genetic analysis is the gold standard for diagnosis of most subtypes. All subtypes display skin manifestations, which are essential to the accurate clinical diagnosis of the condition. Furthermore, cutaneous features can be the first and/or only presenting feature in some cases of EDS and thus understanding these signs is vital for diagnosis. This review focuses on particular cutaneous features of each EDS subtype and their clinical importance. Provision of a specific diagnosis is important for management, prognosis and genetic counselling, often for family members beyond the in idual.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2012
Abstract: To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161 MSH2, n = 222 MSH6, n = 47 and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers. Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC SIR, 20.48 95% CI, 11.71 to 33.27 P .001), endometrial cancer (SIR, 30.62 95% CI, 11.24 to 66.64 P .001), ovarian cancer (SIR, 18.81 95% CI, 3.88 to 54.95 P .001), renal cancer (SIR, 11.22 95% CI, 2.31 to 32.79 P .001), pancreatic cancer (SIR, 10.68 95% CI, 2.68 to 47.70 P = .001), gastric cancer (SIR, 9.78 95% CI, 1.18 to 35.30 P = .009), urinary bladder cancer (SIR, 9.51 95% CI, 1.15 to 34.37 P = .009), and female breast cancer (SIR, 3.95 95% CI, 1.59 to 8.13 P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02 95% CI, 0.33 to 2.39 P = .97). We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.
Publisher: Oxford University Press (OUP)
Date: 24-06-2015
DOI: 10.1093/JNCI/DJV170
Publisher: Wiley
Date: 06-2017
DOI: 10.1111/IMJ.13429
Abstract: Gorlin syndrome (nevoid basal cell carcinoma syndrome) is a rare genetic predisposition to basal cell carcinomas (BCC), keratocysts of the jaw and calcification of the falx cerebri among other clinical features. With the advent of sonic hedgehog inhibitors for the treatment of BCC, it is timely to establish a cohort of in iduals with Gorlin syndrome and collect standardised phenotypic information on these in iduals. Moreover, the health-related quality of life (QoL) in in iduals with Gorlin syndrome is not well studied. To establish a Victorian cohort of Gorlin syndrome and study the QoL in these in iduals. Phenotypic data were obtained by reviewing medical records of in iduals attending two major tertiary/quaternary genetic referral centres in Victoria, followed by telephone or face-to-face interviews where possible. QoL information was obtained utilising the AQoL-6D quality of life survey form. The median number of BCC in the 19 in iduals studied was 17.5 (interquartile range 3-70). The number of patients with ≥100 BCC in this group was similar to a previously described national cohort (22.2 vs 27% respectively). A total of 58% of referrals to the genetics clinics originated from maxillofacial surgeons and 42% from dermatologists. In iduals with ≥100 BCC had worse median QoL scores compared to those with <100 BCC (36 vs 29, P-value of 0.031). The clinical features in our cohort were congruent with those previously described in Australia. The QoL is adversely correlated with increased BCC burden.
Publisher: Elsevier BV
Date: 05-2008
Publisher: Springer Science and Business Media LLC
Date: 22-04-2015
Publisher: Wiley
Date: 02-06-2016
DOI: 10.1002/IJC.30197
Publisher: Springer Science and Business Media LLC
Date: 29-03-2015
DOI: 10.1007/S10689-015-9797-9
Abstract: Women with a BRCA1/2 gene mutation face complex risk management decisions and communication issues that can lead to increased levels of distress and unmet needs. We describe the implementation of a peer-support program that aims to reduce distress among women with a BRCA1/2 mutation, including peer and support recipient satisfaction with the program, challenges and lessons learnt. Participants with a BRCA1/2 mutation were matched with a trained peer volunteer (also a mutation carrier) to have regular one-on-one phone calls, over 4 months. Details of the calls, including topics discussed, time spent and number, were collected. Peers and recipients completed surveys assessing how they felt the contact went, satisfaction with the program, and preferences for matching. Satisfaction with the program was high for both peers and recipients. 80% of pairs ended contact through mutual agreement. Peers and recipients differed in the importance placed on age and surgery experience to determine matches. The most challenging aspect of the program for peers was difficulty in contacting recipients. Peer support for women with a BRCA1/2 mutation is feasible. However, to encourage continued involvement by peers and recipients greater flexibility in the method and delivery of contact is needed. We advocate the use of text-messaging and/or email as mechanisms for pairs to arrange and maintain contact. These strategies should be in addition to, rather than replacing, calls. A mixed medium intervention, where recipients can tailor the method of communication to suit their needs, may be preferable and effective, though this would need to be tested.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Wiley
Date: 08-0012
DOI: 10.1111/AJD.12239
Abstract: Mal de Meleda is a rare autosomal recessive genodermatosis caused by mutations in the ARS B (SLURP1) gene, with possible founder effects in the Mediterranean and Adriatic regions. We report an affected in idual from Indonesia without known consanguinity in the family, suggesting that SLURP1 gene mutations are ubiquitous. Recognition of the phenotype can be confirmed by genetic testing, thus facilitating genetic counselling.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 05-02-2015
DOI: 10.1002/AJMG.A.36917
Abstract: We report on a child with two cardiac rhabdomyomas. Initially, a diagnosis of Tuberous Sclerosis Complex (TSC) syndrome was suspected, although this could neither be confirmed clinically nor genetically. Coincidentally, Birt Hogg Dubé syndrome (BHD) had been previously diagnosed in members of the extended family this prompted a diagnostic re-evaluation of the child who was found to have the known family FLCN mutation. We recommend consideration of cardiac rhabdomyomas as part of the clinical BHD spectrum.
Publisher: Wiley
Date: 30-08-2014
DOI: 10.1007/S10897-013-9643-X
Abstract: We present a case where an apparently straightforward Lynch syndrome predictive genetic test of DNA from a blood s le from a woman yielded an unexpected result of X/Y chromosome imbalance. Furthermore, it demonstrates the complexities of genetic testing in people who have had bone marrow transplants. This highlights the potential for multiple ethical and counselling challenges, including the inadvertent testing of the donor. Good communication between clinics and laboratories is essential to overcome such challenges and to minimise the provision of false results.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.JOCN.2015.05.002
Abstract: We evaluated the prevalence of epilepsy in a cohort of patients who suffered a sudden unexpected death (SUDEP), and determined the proportion of the deaths that were related to an identifiable underlying familial cardiac pathology. Epilepsy is common in people who experience a sudden unexpected death, with approximately a quarter having identifiable familial electrophysiological abnormalities. Familial cardiac pathology may be an important cause of SUDEP. A retrospective evaluation was performed of 74 families that were referred to the Royal Melbourne Hospital Cardiac Genetic Clinic over a 5 year period for investigation following a family member's sudden, presumed cardiac, death. This state-wide referral clinic includes all patients who have died from a sudden unexpected death in whom the cause of death is unascertained. An epilepsy diagnosis was categorised as either definite, probable, possible or unlikely. The family members underwent comprehensive clinical evaluations and investigations in an attempt to identify a familial cardiac cause for the sudden unexpected death. Our findings suggest that systematic referral to a cardiac genetics service is warranted for the first degree relatives of people with epilepsy who experience a sudden unexplained death, for further evaluation and to identify those who are at higher risk for sudden death. Interventions may then be instituted to potentially reduce this risk.
Publisher: Wiley
Date: 28-01-2016
DOI: 10.1111/AJD.12233
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.EJMG.2017.10.020
Abstract: To explore clinical features and relationship with positive mutation ascertainment in inherited heart diseases in order to develop a clinical tool to assist identification of in iduals in whom to offer genetic testing. A clinical tool that increases pre test probability of mutation detection would have the benefits of improving patient counselling, prioritising cases for MPS and allowing equity in decision making. Consecutive MPS mutation detection testing cases were identified (September 2014 - December 2015, n = 126). Cases were scored for the presence of pre-determined clinical and family history variables, blinded to MPS results. Subsequent unblinding allowed ascertainment of the odds ratio (OR) between these clinical variables and positive mutation detection. A clinical tool was developed and variables with higher OR association were given a higher weighting. The mean score in the cohort was 3.94: mutation positive subgroup 4.74, and mutation negative subgroup: 3.49 (t-test, p < 0.0001). The clinical tool was validated in a cohort of 40 patients. There was a strong linear correlation between increasing clinical tool score and probability of detecting a mutation (r Clinical information on probands and their family history allows identification of in iduals with a greater chance of positive mutation detection. This improves pre test counselling, allows equitable identification of in iduals in whom to offer cardiac genetic testing and can be calibrated to a predictable ratio of positive mutation and missed opportunity cases for in idual health services.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2016
DOI: 10.1007/S10689-015-9829-5
Abstract: Incidental findings are inevitable as clinical research and practice transitions from a single gene approach to a genomic approach. A novel deletion of the Fumarate Hydratase (FH) gene was identified in a 22 year old male who underwent a molecular karyotype as part of an autism spectrum disorder research project. This unexpected result implies a predisposition to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a rare, autosomal dominant condition and has unforeseen implications for him and his family. We review the typical features and management of HLRCC and discuss the challenges that face health professionals, as genetic testing advances and becomes more accessible.
Publisher: EDP Sciences
Date: 04-2023
DOI: 10.1051/0004-6361/202244798
Abstract: In the past few years, we have undertaken an extensive investigation of star clusters and their stellar populations in the Large and Small Magellanic Clouds (LMC and SMC) based on archival images collected with the Hubble Space Telescope. We present photometry and astrometry of stars in 101 fields observed with the Wide Field Channel of the Advanced Camera for Surveys and the Ultraviolet and Visual Channel and the Near-Infrared Channel of Wide Field Camera 3. These fields comprise 113 star clusters. We provide differential-reddening maps for those clusters with significant reddening variations across the field of view. We illustrate various scientific outcomes that arise from the early inspection of the photometric catalogs. In particular, we provide new insights into the extended main-sequence turnoff (eMSTO) phenomenon: (i) We detected eMSTOs in two clusters, KMHK 361 and NGC 265, which had no previous evidence of multiple populations. This finding corroborates the conclusion that the eMSTO is a widespread phenomenon among clusters younger than ∼2 Gyr. (ii) The homogeneous color-magnitude diagrams (CMDs) of 19 LMC clusters reveal that the distribution of stars along the eMSTO depends on cluster age. (iii) We discovered a new feature along the eMSTO of NGC 1783, which consists of a distinct group of stars on the red side of the eMSTO in CMDs composed of UV filters. Furthermore, we derived the proper motions of stars in the fields of view of clusters with multi-epoch images. Proper motions allowed us to separate the bulk of bright field stars from cluster members and investigate the internal kinematics of stellar populations in various LMC and SMC fields. As an ex le, we analyze the field around NGC 346 to disentangle the motions of its stellar populations, including NGC 364 and BS 90, young and pre-main-sequence stars in the star-forming region associated with NGC 346, and young and old field stellar populations of the SMC. Based on these results and the fields around five additional clusters, we find that young SMC stars exhibit elongated proper-motion distributions that point toward the LMC, thus providing new evidence for a kinematic connection between the LMC and SMC.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1053/J.GASTRO.2006.03.046
Abstract: Hyperplastic polyposis syndrome (HPS) is defined phenotypically with multiple, large and/or proximal hyperplastic polyps. There is no known germ-line predisposition. We aimed to characterize the clinicopathologic features of 38 patients with HPS and explore the role of germ-line mutations in the base excision repair genes MBD4 and MYH. Utilizing clinical databases of The Royal Melbourne Hospital Bowel Cancer Surveillance Service and the Familial Cancer Clinic, 38 patients with HPS were recruited. The patients were analyzed for age at first diagnosis, features of hyperplastic polyposis, family histories of polyposis and colorectal cancer (CRC), coexisting adenomas, serrated adenomas, incidence of CRC, and microsatellite instability in the tumours. Mutation analysis of MBD4 and MYH were performed. Serrated adenomas were common (26%), and 19 (50%) of the 38 patients had a first-degree relative with CRC. Family history of HPS was uncommon, with only 2 cases found. Ten patients developed CRC, and 3 required surgery for polyposis. No pathogenic mutations in MBD4 were detected in the 27 patients tested, but 6 single nucleotide polymorphisms of uncertain functional significance were identified. Pathogenic biallelic MYH mutations were detected in 1 patient. Mutations in MBD4 are unlikely to be implicated in HPS MYH mutations should be studied, especially when adenomas occur in the same patient. The clinical, histopathologic, and molecular findings of this study should contribute to our understanding of HPS and its relationship to the serrated neoplasia pathway.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.RBMO.2013.01.004
Abstract: FSH receptor (FSHR) gene variants have been associated with premature ovarian failure (POF). Genomic DNA from New Zealand women with POF (n=80) and control women (n=80) was screened for variants in FSHR exons 7 and 10. FSHR exon 7 variants, including the c.566C>T Finnish founder mutation (p.Ala189Val), were not detected. Previously reported FSHR exon 10 polymorphisms were identified in both groups with similar allelic distributions. A novel heterozygous FSHR exon 10 variant c.1411A>T, p.Ile471Phe was observed in one woman with a family history of POF, but not her affected siblings. It is concluded that variants in exons 7 and 10 of FSHR are not frequently associated with the development of POF in the New Zealand population.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2019
DOI: 10.1038/S41416-019-0580-9
Abstract: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1 , 928 in MSH2 , 230 in MSH6 , 106 in PMS2 , 22 in EPCAM ) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92 95% CI, 1.03–3.58) and high cholesterol (HR 1.76 CI 1.23–2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.
Publisher: Elsevier BV
Date: 05-2005
Publisher: Springer Science and Business Media LLC
Date: 23-12-2013
DOI: 10.1007/S10689-012-9596-5
Abstract: Distress levels among female BRCA1/2 mutation carriers can be similar to levels found among breast cancer patients. While psychological distress has been associated with unmet needs among cancer patients no study has examined this among BRCA1/2 mutation carriers. The objectives of this study were to: (1) describe the unmet support needs of women with a known BRCA1/2 mutation, (2) determine how unmet needs are related to psychological distress, and (3) identify variables that predict level of unmet need and distress. Female BRCA1/2 mutation carriers were identified through Familial Cancer Centers in 3 Australian states. Two-hundred and seventy-nine participants completed surveys assessing need for help on 16 information and support items. The Impact of Events Scale assessed genetic test related distress. Participants reported an average of 5.4 (SD = 4.9) moderate to very high unmet needs. Twenty-one percent had scores indicating moderate distress, and 13 % indicating severe distress. Younger age (t = -3.34 p < 0.01), not having someone to confide in about the gene mutation (t = 2.57 p = 0.01) and shorter time since notification of mutation status (t = -2.49 p = 0.01) were associated with higher unmet need scores in linear regression analyses. Greater number of unmet needs was associated with a greater likelihood of moderate to severe levels of distress (OR = 1.19 p < 0.01) in logistic regression analyses. Identifying appropriate interventions that target unmet needs among younger women and those with no confidante may help to reduce distress. Interventions that provide an opportunity for women to confide in someone, such as Peer support programs, may be one way of meeting the emotional needs of this population.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2017
DOI: 10.1007/S10689-016-9961-X
Abstract: An apparently balanced t(2 )(q37.3 q13.2) translocation that appears to segregate with renal cell carcinoma (RCC) has indicated potential areas to search for the elusive genetic basis of clear cell RCC. We applied Hi-Plex targeted sequencing to analyse germline DNA from 479 in iduals affected with clear cell RCC for this breakpoint translocation and genetic variants in neighbouring genes on chromosome 2, ACKR3 and COPS8. While only synonymous variants were found in COPS8, one of the missense variants in ACKR3:c.892C>T, observed in 4/479 in iduals screened (0.8%), was predicted likely to damage ACKR3 function. Identification of causal genes for RCC has potential clinical utility, where risk assessment and risk management can offer better outcomes, with surveillance for at-risk relatives and nephron sparing surgery through earlier intervention.
Publisher: Oxford University Press (OUP)
Date: 11-08-2014
DOI: 10.1093/JNCI/DJU180
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 09-1991
Publisher: JMIR Publications Inc.
Date: 30-08-2017
DOI: 10.2196/MHEALTH.7014
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CLCC.2018.01.001
Abstract: Colorectal cancer (CRC), one of the most common cancers, is a major public health issue globally, especially in Westernized countries. Up to 35% of CRCs are thought to be due to heritable factors, but currently only 5% to 10% of CRCs are attributable to high-risk mutations in known CRC susceptibility genes, predominantly the mismatch repair genes (Lynch syndrome) and adenomatous polyposis coli gene (APC familial adenomatous polyposis). In this era of precision medicine, high-risk mutation carriers, when identified, can be offered various risk management options that prevent cancers and improve survival, including risk-reducing medication, screening for early detection, and surgery. The practice of clinical genetics is currently transitioning from phenotype-directed single gene testing to multigene panels, now offered by numerous providers. For CRC, the genes included across these panels vary, ranging from well established, clinically actionable susceptibility genes with quantified magnitude of risk, to genes that lack extensive validation or have less evidence of association with CRC and, therefore, have minimal clinical utility. The current lack of consensus regarding inclusion of genes in CRC panels presents challenges in patient counseling and management, particularly when a variant in a less validated gene is identified. Furthermore, there remain considerable challenges regarding variant interpretation even for the well established CRC susceptibility genes. Ironically though, only through more widespread testing and the accumulation of large international data sets will sufficient information be generated to (i) enable well powered studies to determine if a gene is associated with CRC susceptibility, (ii) to develop better models for variant interpretation and (iii) to facilitate clinical translation.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Mary Ann Liebert Inc
Date: 19-03-2000
Abstract: PCR lification of the CAG repeat in exon 1 of the IT15 gene is routinely undertaken to confirm a clinical diagnosis of Huntington disease (HD) and to provide predictive testing for at-risk relatives of affected in iduals. Our studies have detected null alleles on the chromosome carrying the expanded repeat in three of 91 apparently unrelated HD families. Sequence analysis of these alleles has revealed the same mutation event, leading to the juxtaposition of uninterrupted CAG and CCG repeats. These data suggest that a mutation-prone region exists in the IT15 gene bounded by the CAG and CCG repeats and that caution should be exercised in designing primers that anneal to the region bounded by these repeats. Two of the HD families segregated null alleles with expanded uninterrupted CAG repeats at the lower end of the zone of reduced penetrance. The expanded repeats are meiotically unstable in these families, although this instability is within a small range of repeat lengths. The haplotypes of the disease-causing chromosomes in these two families differ, only one of which is similar to that reported previously as being specific for new HD mutations. Finally, no apparent mitotic instability of the uninterrupted CAG repeat was observed in the brain of one of the HD in iduals.
Publisher: Oxford University Press (OUP)
Date: 09-1991
DOI: 10.1111/J.1365-2230.1991.TB00403.X
Abstract: A young woman presented with renal failure and skin lesions of livedo reticularis (LR) due to primary oxalosis. Primary oxalosis is a rare autosomal-recessive error of metabolism characterized by accumulation of calcium-oxalate crystals in the kidneys, eyes, heart and skin. This unusual cause of intravascular obstruction resulting in livedo reticularis should be considered in patients with renal impairment. An approach to the diagnosis of LR is presented.
Publisher: Springer Science and Business Media LLC
Date: 07-2016
Publisher: Elsevier BV
Date: 1997
DOI: 10.1080/00313029700169494
Abstract: A member of a hereditary non-polyposis colorectal cancer (HNPCC) family developed two colorectal cancers and multiple polyps within four years of a negative colonoscopic examination. One of the cancers was only 4 mm in diameter and showed the gross and endoscopic appearances of a de novo carcinoma. Microscopic examination of multiple levels revealed a mixed hyperplastic polyp/adenoma (mixed polyp) in contiguity with the cancer. The colon harboured additional polyps of which five were tubular adenomas, seven were hyperplastic polyps and seven were mixed polyps (architecturally compatible with hyperplastic polyps but with atypical cytology). Atypical features of the mixed polyps included tripolar mitoses, bizarre chromatin aggregations and multinucleation. One mixed polyp showed DNA microsatellite instability. Under the influence of the mutator defect, hyperplastic polyps may develop atypical or adenomatous features and show progression to carcinoma. Such an alternative morphogenetic pathway could explain the differing molecular and pathological profiles of cancers showing DNA microsatellite instability.
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1086/302408
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2023
DOI: 10.1101/2023.05.18.540731
Abstract: 1 Single-cell RNA-Seq (scRNA-seq) transcriptomics can elucidate gene regulatory networks (GRNs) of complex phenotypes, but raw sequencing observations only provide ”snap-shots” of data and are inherently noisy. scRNA-seq trajectory inference has been utilized to solve for the missing observations, but disentangling complex dynamics of gene-gene interactions at different time points from aggregated data is a non-trivial task and computationally expensive. Here we describe our Non-Stiff Dynamic Invertible Model of CO-Regulatory Networks (NS-DIMCORN) to define the genetic nexus underpinning specific cellular functions using invertible warping of flexible multivariate Gaussian distributions by neural Ordinary differential equations. Our results yield a generative model with unbiased density estimation from RNA-seq read-count data only. This resulted in scalable time-flexible s ling of each gene’s expression level thence allowing ab initio assembly of gene regulatory networks in specific cells. We demonstrate our proposed methodology is superior to the state-of-the-art algorithms in accurately recovering genome-wide functional interactions, whether from synthetic or empirical data. We optimized our algorithm for GPU-based implementation thereby further enhancing the utility of our proposed methodology in comparison to the ten benchmarked methods.
Publisher: BMJ
Date: 07-2000
DOI: 10.1136/GUT.47.1.37
Abstract: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.
Publisher: Elsevier BV
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 28-02-2019
Publisher: BMJ
Date: 24-03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2011
Publisher: Springer Science and Business Media LLC
Date: 09-06-2017
DOI: 10.1038/NCOMMS15724
Abstract: Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P =3.1 × 10 −10 ), 3p22.1 (rs67311347, P =2.5 × 10 −8 ), 3q26.2 (rs10936602, P =8.8 × 10 −9 ), 8p21.3 (rs2241261, P =5.8 × 10 −9 ), 10q24.33-q25.1 (rs11813268, P =3.9 × 10 −8 ), 11q22.3 (rs74911261, P =2.1 × 10 −10 ) and 14q24.2 (rs4903064, P =2.2 × 10 −24 ). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Wiley
Date: 12-1984
Abstract: We have investigated a large Afrikaner kindred in which seven males had ocular albinism and late-onset sensorineural deafness (OASD). The pattern of inheritance of OASD is X-linked recessive. To the best of our knowledge, this association has not previously been reported and in order to establish syndromic identity we describe and discuss the condition in this article.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2011
Publisher: Wiley
Date: 09-06-2017
DOI: 10.1111/BJU.13889
Abstract: To determine whether the use of nephron-sparing surgery (NSS) for treatment of stage 1 renal cell carcinoma (RCC) changed between 2009 and the end of 2013 in Australia. All adult cases of RCC diagnosed in 2009, 2012 and 2013 were identified through the population-based Victorian Cancer Registry. For each identified patient, trained data-abstractors attended treating hospitals or clinician rooms to extract tumour and treatment data through medical record review. Multivariable logistic regression analyses were carried out to examine the significance of change in use of NSS over time, after adjusting for potential confounders. A total of 1 836 patients with RCC were identified. Of these, the proportion of cases with stage 1 tumours was 64% in 2009, 66% in 2012 and 69% in 2013. For T1a tumours, the proportion of patients residing in metropolitan areas receiving NSS increased from 43% in 2009 to 58% in 2012 (P < 0.05), and 69% in 2013 (P < 0.05). For patients residing in non-metropolitan areas, the proportion receiving NSS increased from 27% in 2009 to 49% in 2012, and 61% in 2013 (P < 0.01). Univariable logistic regression showed patients with moderate (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.35-0.94) or severe comorbidities (OR 0.58, 95% CI 0.33-0.99), residing in non-metropolitan areas (OR 0.65, 95% CI 0.47-0.90), were less likely to be treated by NSS, while those attending high-volume hospitals (≥30 cases/year: OR 1.79, 95% CI 1.21-2.65) and those with higher socio-economic status (OR 1.45, 95% CI 1.02-2.07) were more likely to be treated by NSS. In multivariable analyses, patients with T1a tumours in 2012 (OR 2.00, 95% CI 1.34-2.97) and 2013 (OR 3.15, 95% CI 2.13-4.68) were more likely to be treated by NSS than those in 2009. For T1b tumours, use of NSS increased from 8% in 2009 to 20% in 2013 (P < 0.05). This population-based study of the management of T1 renal tumours in Australia found that the use of NSS increased over the period 2009 to 2013. Between 2009 and 2013 clinical practice for the treatment of small renal tumours in Australia has increasingly conformed to international guidelines.
Publisher: Wiley
Date: 18-02-2019
DOI: 10.1002/JGC4.1102
Abstract: Internationally, the practice of offering additional findings (AFs) when undertaking a clinically indicated genomic test differs. In the USA, the recommendation is to include analysis for AFs alongside diagnostic analysis, unless a patient opts-out, whereas European and Canadian guidelines recommend opt-in models. These guidelines all consider the offer of AFs as an activity concurrent with the offer of diagnostic testing. This paper describes a novel two-step model for managing AFs within the healthcare system in Victoria, Australia and presents the study protocol for its evaluation. Adults who have received results of diagnostic whole exome sequencing undertaken within the healthcare system are invited to attend a genetic counseling appointment to consider reanalysis of their stored genomic data for AFs. The evaluation protocol addresses uptake, decision-making, understanding, counseling challenges, and explores preferences for future models of care. Recruitment commenced in November 2017 and will cease when 200 participants have been approached. When the study is concluded, the evaluation results will contribute to the evidence base guiding approaches to counseling and models of care for AFs.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2007
DOI: 10.1007/S00251-006-0184-4
Abstract: Intron 1 of the interferon-gamma (IFNG) gene contains two polymorphisms. The 12 CA-repeat allele of the +875 IFNGCA microsatellite and the T allele of the +A874T single nucleotide polymorphism (SNP) have been associated with increased in vitro IFNG production and a variety of clinical phenotypes. The purpose of this study was to determine whether these polymorphisms influence total serum IgE levels [tsIgE] and the outcome of a hepatitis B virus (HBV) infection. IFNGCA and +A874T were typed in 186 asthmatics of Niuean ancestry and in Polynesian women with a chronic HBV infection (n = 60) and with natural immunity to the HBV (n = 66). The IFNGCA genotype was associated with [tsIgE] in asthmatic children (n = 51, p = 0.004) but not adults (n = 135, p = 0.87). The data were consistent with a co-dominant influence of the 12 CA-repeat allele on high [tsIgE]. The IFNGCA genotype was also associated with the risk for chronic HBV infection (chi (2) = 11.6, p = 0.003) because of a dominant effect of the 12 CA-repeat allele on developing natural immunity in homozygotes (OR = 5.8, p = 0.003) and heterozygotes (OR = 2.7, p = 0.01). Similar associations were found for the T allele of the +A874T SNP. The possibility that these associations were due to linked alleles in the adjacent 783 bp of the promoter and 3'-untranslated region of the IFNG gene was excluded by direct sequencing. In summary, high-IFNG-producing alleles in intron 1 of the IFNG locus are associated with high [tsIgE] in asthmatic children from Niue and with natural immunity to the HBV in Polynesian women. These findings are consistent with a previous report of an association between +875 IFNGCA and [tsIgE] and provide preliminary evidence of a new association with the outcome of an HBV infection.
Publisher: Royal College of General Practitioners
Date: 23-01-2023
Abstract: A risk-stratified approach to colorectal cancer (CRC) screening could result in a more acceptable balance of benefits and harms, and be more cost-effective. To determine the effect of a consultation in general practice using a computerised risk assessment and decision support tool (Colorectal cancer RISk Prediction, CRISP) on risk-appropriate CRC screening. Randomised controlled trial in 10 general practices in Melbourne, Australia, from May 2017 to May 2018. Participants were recruited from a consecutive s le of patients aged 50–74 years attending their GP. Intervention consultations included CRC risk assessment using the CRISP tool and discussion of CRC screening recommendations. Control group consultations focused on lifestyle CRC risk factors. The primary outcome was risk-appropriate CRC screening at 12 months. A total of 734 participants (65.1% of eligible patients) were randomised (369 intervention, 365 control) the primary outcome was determined for 722 (362 intervention, 360 control). There was a 6.5% absolute increase (95% confidence interval [CI] = −0.28 to 13.2) in risk-appropriate screening in the intervention compared with the control group (71.5% versus 65.0% odds ratio [OR] 1.36, 95% CI = 0.99 to 1.86, P = 0.057). In those due CRC screening during follow-up, there was a 20.3% (95% CI = 10.3 to 30.4) increase (intervention 59.8% versus control 38.9% OR 2.31, 95% CI = 1.51 to 3.53, P .001) principally by increasing faecal occult blood testing in those at average risk. A risk assessment and decision support tool increases risk-appropriate CRC screening in those due screening. The CRISP intervention could commence in people in their fifth decade to ensure people start CRC screening at the optimal age with the most cost-effective test.
Publisher: Wiley
Date: 14-01-2017
DOI: 10.1111/AJD.12443
Abstract: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant condition characterised by mucocutaneous pigmented lesions, gastrointestinal polyposis and a significant risk of cancer. Laugier-Hunziker syndrome (LHS) is a benign condition with similar dermatological features, but with no systemic complications. STK 11 gene testing allows clinicians to differentiate between these two disorders. This case report compares the dermatological similarities in four in iduals with PJS or LHS and illustrates the potential benefit of genetic testing. There is > 90% likelihood of identifying a mutation in STK 11 if a patient fulfils the diagnostic criteria for PJS. Lifelong risk management is advised for these in iduals with confirmed PJS. Diagnostic confirmation is important to provide rational management, in particular, endoscopic cancer surveillance, and psychological support. STK 11 testing can confirm those at risk of PJS, who require lifelong surveillance, and possibly release those with a simple dermatosis, such as LHS, from invasive and thus potentially harmful surveillance.
Publisher: Oxford University Press (OUP)
Date: 02-05-2020
DOI: 10.1111/CED.14223
Publisher: Elsevier BV
Date: 09-2019
Publisher: Oxford University Press (OUP)
Date: 2022
DOI: 10.1111/BJD.20664
Publisher: Springer Science and Business Media LLC
Date: 10-05-2011
DOI: 10.1038/BJC.2011.172
Publisher: Wiley
Date: 11-2004
DOI: 10.1111/J.1440-1843.2004.00601.X
Abstract: The aim of this study was to identify asthma phenotypes in patients of Niue Island ancestry that might be suitable for susceptibility gene mapping studies. Two hundred and sixteen Niue Islanders with physician-diagnosed asthma that was not secondary to other medical conditions were recruited through community organisations. Fifty-one of the subjects with asthma were resident on Niue Island and 165 in New Zealand. Each subject was interviewed and tested for atopy, serum [IgE] (5% quantile, median, 95% quantile) and lung function. There were two groups of subjects defined by an age of onset of asthma less than 12 years of age (childhood-onset, boys:girls 64:65) and greater than 12 years of age (adult-onset, men:women 11:76). A positive response (wheal > 3 mm) to at least one aeroallergen was seen in 181 patients, with 168/181 (92.8%) responding to house dust mite. Twenty-eight subjects with asthma were non-atopic (no detectable wheal) and the atopy status of seven subjects with asthma could not be determined (wheal < 3 mm). In childhood-onset asthma, serum IgE levels were higher (P < 0.0001) in subjects with atopic than in subjects with non-atopic asthma. In adult-onset asthma, serum IgE levels were higher (P < 0.0001) in subjects with atopic asthma than in either subjects with non-atopic asthma or matched non-atopic subjects without asthma. The asthma phenotypes in Niue Island and New Zealand residents were similar. Both atopic and non-atopic asthma phenotypes exist in Niue Islanders resident in Niue and New Zealand. The potential for mapping asthma susceptibility genes in this isolated population is discussed.
Publisher: Wiley
Date: 18-11-2003
Publisher: Hindawi Limited
Date: 10-04-2002
DOI: 10.1002/HUMU.10067
Abstract: Hereditary diffuse gastric cancer (HDGC) is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the gene for the cell-to-cell adhesion protein E-cadherin (CDH1). Here, we describe the search for CDH1 mutations in 10 newly identified gastric cancer families. Seven of 10 families met the clinical criteria for HDGC. Germline mutations were identified in four of these seven families and one family that was borderline for the clinical criteria. Of the mutations identified in the five new families, four were previously unreported and consisted of two frameshift and two donor splice site mutations. One splice site mutation occurred at the 100% conserved +1 position. The second splice site mutation occurred at the +5 position and was shown to lead to abnormal splicing. Additional CDH1 variants detected include the heterozygous -160 C-->A promoter polymorphism, which has previously been reported to be associated with decreased CDH1 transcription. We, however, found this polymorphism to be common in a control population, suggesting that a major role for this polymorphism in gastric cancer susceptibility is unlikely.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1007/S10689-018-0073-7
Abstract: Many cancer predisposition syndromes are preceded or accompanied by a range of typical skin signs. Gorlin syndrome is a rare multisystem inherited disorder which can predispose to basal cell carcinomas (BCCs), childhood medulloblastomas in addition to various developmental abnormalities the majority of cases are due to mutations in the PTCH1 gene. Approximately 5% of cases have been attributed to a mutation in the SUFU gene. Certain phenotypic features have been identified as being more prevalent in in iduals with a SUFU mutation such as childhood medulloblastoma, infundibulocystic BCCs and trichoepitheliomas. Recently hamartomatous skin lesions have also been noted in families with childhood medulloblastoma, a "Gorlin like" phenotype and a SUFU mutation. Here we describe a family previously diagnosed with Gorlin syndrome with a novel SUFU splice site deleterious genetic variant, who have several dermatological features including palmar sclerotic fibromas which has not been described in relation to a SUFU mutation before. We highlight the features more prominent in in iduals with a SUFU mutation. It is important to note that emerging therapies for treatment of BCCs in patients with a PTCH1 mutation may not be effective in those with a SUFU mutation.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.CGH.2005.12.003
Abstract: Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable--the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1% this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for in iduals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1093/HMG/3.1.197
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2013
Abstract: Summary evidence on the effectiveness of quality improvement interventions (QIIs) directed at cancer specialists is needed for two reasons. First, there are some innovations over which only cancer specialists have control (eg, surgical technique or chemotherapy regimen). Second, implementation of QIIs has opportunity costs the time and money spent on an ineffective QII might be better spent on direct patient care. Medical Subject Headings and text words for “quality improvement” were combined with those for “neoplasm” to search MEDLINE, PsycINFO, CINAHL, and EMBASE from January 1990 to August 2012 for studies of QIIs directed at cancer specialists (eg, medical/radiation oncologist, surgeon). All study designs were included. Five thousand seven hundred eighty-one articles were screened, but only 12 met the inclusion criteria, including three cluster randomized controlled trials (cRCTs), seven uncontrolled before-and-after comparisons, and two cross-sectional studies. All 12 studies were conducted in response to concerns about quality of care. No cRCT showed a benefit of the QIIs tested. Some uncontrolled before-and-after and cross-sectional studies reported a benefit from the QII, but these studies are difficult to interpret because of concerns about uncontrolled confounding. Interventions in all studies were multifaceted, but descriptions of different components were limited, and only one study examined their separate impact. The published evidence about how to facilitate timely and consistent adoption of new clinical knowledge by cancer specialists into everyday clinical practice is thin. More investment is needed in research about the solution (QIIs) to match the investment in research about the problem (inconsistent/slow adoption of innovative cancer treatments).
Publisher: American Medical Association (AMA)
Date: 07-07-2015
Publisher: Springer Science and Business Media LLC
Date: 10-12-2010
DOI: 10.1007/S10689-010-9413-Y
Abstract: Chromosome translocations involving chromosome 3 have previously been associated with the development of renal cell carcinoma. In this report we describe an Ashkenazi Jewish family with a previously unreported balanced constitutional translocation (t(2 )(q37.3 q13.2)) segregating with the development of clear cell renal carcinomata in three family members spanning two generations. We outline the difficulties with the clinical utility of this finding for genetic counselling and risk management strategies. We suggest that an additional renal cancer susceptibility gene may exist at 3q13.2, and review known breakpoints in the autosomes which are associated with clear cell renal cell carcinoma.
Publisher: Mary Ann Liebert Inc
Date: 11-2017
Publisher: Oxford University Press (OUP)
Date: 13-11-2019
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1038/S41523-019-0140-8
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Public Library of Science (PLoS)
Date: 03-01-2019
Publisher: Wiley
Date: 05-1991
DOI: 10.1111/J.1399-0004.1991.TB03039.X
Abstract: Piebaldism is a disorder in which the major clinical features are patchy hypopigmentation of the skin and a white forelock. The manifestations of piebaldism overlap with those of other genodermatoses, in particular the Waardenburg syndrome, and it is uncertain whether piebaldism is a distinct entity. We have documented a family in which seven affected members in three generations have gross piebaldism without any additional stigmata. The intrafamilial phenotypic consistency is suggestive that this autosomal dominant disorder has independent syndromic status. Linkage studies using conventional gene markers failed to identity the locus of the faulty gene.
Publisher: Wiley
Date: 04-01-2005
DOI: 10.1002/AJMG.A.30507
Publisher: Oxford University Press (OUP)
Date: 02-2013
DOI: 10.1093/JNCI/DJS525
Publisher: Wiley
Date: 07-08-2012
DOI: 10.1002/AJMG.A.35538
Abstract: A novel duplication of Xp is described. A 20-year-old man had minor anomalies ichthyosis, congenital heart defect, varicose veins, and hypogonadotropic hypogonadism. He had an interstitial duplication of approximately 2.8 Mb from chromosome region Xp22.31p22.2. His similarly affected brother and asymptomatic mother were shown to carry the same duplication. Knowledge about this duplication and its resultant phenotype will add to our understanding of the role of X chromosome duplications.
Publisher: BMJ
Date: 30-12-2010
Publisher: Wiley
Date: 19-09-2016
DOI: 10.1002/AJMG.A.37952
Abstract: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disease characterised by benign cutaneous lesions, pulmonary cysts, and an increased risk of renal tumors. This rare condition is due to a mutation in the folliculin (FLCN) gene on chromosome 17q11.2, which has a role in the mechanistic/mammalian target of rapamycin (mTOR) signaling pathway of tumorigenesis. This case illustrates a patient with BHD and a renal angiomyolipoma, a neoplastic lesion not usually associated with BHD but common in Tuberous Sclerosis Complex (TSC). There is both clinical and molecular overlap between BHD and TSC, which may arise from similarities in function of the TSC and FLCN proteins in the mTOR pathway this case further demonstrates this potential correlation. © 2016 Wiley Periodicals, Inc.
Publisher: Hindawi Limited
Date: 22-11-2010
DOI: 10.1002/HUMU.21379
Publisher: Springer Science and Business Media LLC
Date: 02-11-2015
DOI: 10.1007/S10689-014-9763-Y
Abstract: We describe a young patient with typical neurofibromatosis type 1 on the basis of a mutation in the NF1 gene, who was diagnosed with a unilateral vestibular schwannoma caused by a somatic mutation in the NF2 gene. This combination has not been described before. This report highlights the requirement for ongoing surveillance regarding other manifestations of neurofibromatosis type 2 in such patients, as mosaicism cannot be ruled out. In addition to the NF1 mutation, the NF2 mutation should be considered in such cases if pre-implantation genetic diagnosis in undertaken.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2020
Publisher: Public Library of Science (PLoS)
Date: 31-05-2012
Publisher: Elsevier BV
Date: 11-1993
Abstract: X-linked ocular albinism with late-onset sensorineural deafness (OASD) is an autonomous disorder that poses significant clinical problems, causing affected in iduals to be blind and deaf by early middle age. Classical X-linked ocular albinism (without deafness OA1) has recently been linked to markers in the Xp22.2-Xp22.3 region of the human genome. In the present report, a large South African family with OASD was investigated at the molecular level and tight linkage was found to the DXS452 locus at Xp22.3 using 25 informative meioses, with a maximum lod score of 7.1 at a recombination fraction of 0.00. These findings suggest that OA1 and OASD are allelic variants or that they may be due to contiguous gene defects.
Publisher: BMJ
Date: 02-2016
Publisher: Wiley
Date: 08-12-2023
DOI: 10.1002/JGC4.1659
Abstract: Genetic counseling plays a critical role in supporting in iduals and their families' adaption to psychiatric conditions, addressing the multifactorial nature of these conditions in a personally meaningful and empowering way. Yet data related to the practice and attitudes of Australian genetic counselors about psychiatric genetic counseling (PGC) is limited. This survey investigated the practice of Australian genetic counselors, and their attitudes toward PGC. Genetic counselors ( N = 393) were invited to participate in an anonymous online survey between March and May 2022. Forty‐four genetic counselors (response rate = 11%) from Australia and New Zealand responded. No respondents practice in psychiatric genetics as their speciality area most respondents do not see any patients where the primary indication is a personal and/or family history of psychiatric disorders (91%). Greater than half of respondents (56%) believed there was sufficient evidence to support PGC, and 64% enquire about personal and/or family history of psychiatric disorders, but only 25% provide genetic counseling on this topic. Most respondents do not feel confident providing risk assessments for psychiatric disorders (72%), while the majority expressed interest in attending specialist training (95%), and in incorporating PGC into future practice (77%). Australian genetic counselors would benefit from psychiatric genetic education and training, and establishment of specialized PGC services would address this gap in patient care, while providing opportunities for genetic counselors to gain skills and experience in PGC.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2014
Abstract: To assess the effectiveness of a telephone-based peer-delivered intervention in reducing distress among women with a BRCA1 or BRCA2 gene mutation. The intervention involved trained peer volunteers contacting women multiple times over a 4-month period to provide informational, emotional, and practical support. Three hundred thirty-seven participants completed the baseline questionnaire, and those reporting interest in talking to other mutation carriers were randomly assigned to either the usual care group (UCG n = 102) or the intervention group (IG n = 105). Participants and researchers were not blinded to group allocation. Two follow-up questionnaires were completed, one at the end of the intervention (4 months after random assignment, time 2) and one 2 months later (time 3). Outcomes included breast cancer distress (primary outcome), unmet information needs, cognitive appraisals about mutation testing, and feelings of isolation. There was a greater decrease in breast cancer distress scores in the IG than UCG at time 2 (mean difference, −5.96 95% CI, −9.80 to −2.12 P = .002) and time 3 (mean difference, −3.94 95% CI, −7.70 to −0.17 P = .04). There was a greater reduction in unmet information needs in the IG than UCG (P .01), with unmet needs being lower in the IG than UCG at time 2. There was a greater reduction in Cognitive Appraisals About Genetic Testing stress subscale scores in the IG than UCG (P = .02), with significantly lower scores among the IG than UCG at time 2 (P .01). The intervention is effective in reducing distress and unmet information needs for this group of women. Identifying strategies for prolonging intervention effects is warranted.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2019
DOI: 10.1007/S10689-019-00120-0
Abstract: The AXIN2 gene, like APC, plays a role in the Wnt signalling pathway involved in colorectal tumour formation. Heterozygous mutations in AXIN2 have been shown to cause ectodermal dysplasia (including tooth agenesis, or more specifically, oligodontia), and, in some carriers, colorectal cancer and/or adenomatous polyposis develops. There is a paucity of published AXIN2 families making genotype-phenotype (polyposis, colorectal cancer and oligodontia) correlations challenging. In this case report we describe a family with c.1972delA, p.Ser658Alafs*31 nonsense variant in AXIN2 where the three confirmed carriers presented with both oligodontia and colorectal adenomatous polyposis mean number of teeth missing in carriers was 16.5 (range 11-22) and mean number of polyps in carriers was 49 (range 5->100, polyps were predominantly adenomatous). This highlights the importance of confirming phenotypic information in familial polyposis, to guide appropriate genetic investigations, as well as providing additional phenotypic and penetrance data to aid in clinical risk management recommendations. Our experience supports the inclusion of AXIN2 on panels for testing of patients with polyposis.
Publisher: Wiley
Date: 08-1990
Abstract: Boomerang dysplasia is a recently delineated form of neonatally lethal dwarfism. A fourth case has been investigated and an increased range of phenotypic manifestations is documented in this article. So far all affected infants have been males and X-linked recessive inheritance is possible. Diagnostic criteria for Boomerang dysplasia are outlined.
Publisher: BMJ
Date: 07-01-2021
DOI: 10.1136/GUTJNL-2019-320462
Abstract: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. The combination of mutational signatures SBS18 and SBS36 contributing % of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10 -5 ), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99) however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
Publisher: Oxford University Press (OUP)
Date: 10-04-2016
DOI: 10.1093/IJE/DYW036
Publisher: Wiley
Date: 04-1992
Publisher: Springer Science and Business Media LLC
Date: 29-01-2013
Publisher: Oxford University Press (OUP)
Date: 30-10-2019
Abstract: Unexplained sudden cardiac death (SCD) may be attributable to cardiogenetic disease. Presence or absence of autopsy anomalies detected following premature sudden death direct appropriate clinical evaluation of at-risk relatives towards inherited cardiomyopathies or primary arrhythmia syndromes, respectively. We investigated the relevance of non-diagnostic pathological abnormalities of indeterminate causality (uncertain) such as myocardial hypertrophy, fibrosis, or inflammatory infiltrates to SCD. At-risk relatives of unexplained SCD cases aged 1-64 years without prior cardiac disease (n = 98) with either normal and negative (40%, true sudden arrhythmic death syndrome SADS) or isolated non-diagnostic (60%, uncertain sudden unexplained death SUD) cardiac histological autopsy findings at a central forensic pathology unit were referred to the regional unexplained SCD clinic for clinical cardiac phenotyping. Uncertain SUD were older than true SADS cases (31.8 years vs. 21.1 years, P < 0.001). A cardiogenetic diagnosis was established in 24 families (24.5%) following investigation of 346 referred relatives. The proportions of uncertain SUD and true SADS explained by familial cardiogenetic diagnoses were similar (20% vs. 31%, P = 0.34, respectively), with primary arrhythmia syndromes predominating. Unexplained SCD cases were more likely than matched non-cardiac premature death controls to demonstrate at least one uncertain autopsy finding (P < 0.001). Primary arrhythmia syndromes predominate as familial cardiogenetic diagnoses amongst both uncertain SUD and true SADS cases. Non-diagnostic or uncertain histological findings associate with SUD, though cannot be attributed a causative status. At-risk relatives of uncertain SUD cases should be evaluated for phenotypic evidence of both ion channel disorders and cardiomyopathies.
Publisher: American Medical Association (AMA)
Date: 08-2009
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.SCITOTENV.2018.08.032
Abstract: With a growing number of available datasets especially from satellite remote sensing, there is a great opportunity to improve our knowledge of the state of the hydrological processes via data assimilation. Observations can be assimilated into numerical models using dynamics and data-driven approaches. The present study aims to assess these assimilation frameworks for integrating different sets of satellite measurements in a hydrological context. To this end, we implement a traditional data assimilation system based on the Square Root Analysis (SQRA) filtering scheme and the newly developed data-driven Kalman-Takens technique to update the water components of a hydrological model with the Gravity Recovery And Climate Experiment (GRACE) terrestrial water storage (TWS), and soil moisture products from the Advanced Microwave Scanning Radiometer - Earth Observing System (AMSR-E) and Soil Moisture and Ocean Salinity (SMOS) in a 5-day temporal scale. While SQRA relies on a physical model for forecasting, the Kalman-Takens only requires a trajectory of the system based on past data. We are particularly interested in testing both methods for assimilating different combination of the satellite data. In most of the cases, simultaneous assimilation of the satellite data by either standard SQRA or Kalman-Takens achieves the largest improvements in the hydrological state, in terms of the agreement with independent in-situ measurements. Furthermore, the Kalman-Takens approach performs comparably well to dynamical method at a fraction of the computational cost.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-10-2018
Abstract: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%–24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome–associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2016
DOI: 10.1158/1078-0432.CCR-15-2765
Abstract: Purpose: Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C& T. We sought evidence for an association between the rs16906252C& T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues. Experimental Design: By applying a molecular pathologic epidemiology case–control study design, associations between rs16906252C& T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test s le comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation s le comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C& T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues. Results: An association between rs16906252C& T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney s le was observed [OR, 3.3 95% confidence interval (CI), 2.0–5.3 P & 0.0001], which was replicated in the ACCFR s le (OR, 4.0 95% CI, 2.4–6.8 P & 0.0001). The T allele demonstrated about 2.5-fold reduced transcription in normal colorectal mucosa from cases and controls and was selectively methylated in a minority of normal cells, indicating that rs16906252C& T represents an expression and methylation quantitative trait locus. Conclusions: We provide evidence that rs16906252C& T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res 22(24) 6266–77. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
Publisher: Wiley
Date: 12-2009
Publisher: BMJ
Date: 08-1989
DOI: 10.1136/JMG.26.8.511
Abstract: The question of genetic heterogeneity in tuberous sclerosis (TSC) was addressed by genetic linkage studies in eight affected families using nine polymorphic markers (EFD126.3, MCT136, ABO, ABL, AK1, and MCOA12 from distal 9q, and PBGD, MCT128.1, and 1CJ52.208M from distal 11q). The data as a whole supported a TSC locus on distal 9q, the peak lod score on multipoint analysis being 3.77 at 6 cM proximal to the Abelson oncogene locus (ABL). However, analysis of two point lod scores using the HOMOG programs showed significant evidence for genetic heterogeneity (p = 0.01), linkage to ABL being unlikely in one family. After exclusion of the unlinked family, multipoint analysis gave a peak lod score of 6.1 in the vicinity of ABL. The family unlinked to ABL showed no recombinants with two chromosome 11 probes, but was too small to provide significant evidence for linkage. Genetic heterogeneity in TSC will complicate efforts to clone the causative genes and severely limit the use of linked probes for carrier detection and prenatal diagnosis.
Publisher: Oxford University Press (OUP)
Date: 03-02-2010
DOI: 10.1093/JNCI/DJP473
Publisher: Springer Science and Business Media LLC
Date: 07-10-2015
DOI: 10.1007/S10689-014-9752-1
Abstract: Medulloblastoma tumours may arise sporadically or as part of an inherited syndrome. A subset of children with medulloblastoma carry germline and somatic mutations in the SUFU tumour suppressor gene located at 10q24. We report a 55 year old woman referred for investigation on the basis of skin lesions and a family history of two children from different unions with medulloblastoma. Examination of our patient revealed facial papules (classified as benign folliculosebaceous hamartomatous lesions) and dysmorphology (macrocephaly, hypertelorism and prognathism). She reported her father and her son share the same dermatological features photographs of the son display hypertelorism. Sequencing in our patient revealed a splice-site mutation in intron 6 of SUFU (c. 756+1G>A), predicted to lead to skipping of exon 6. We suggest that the emerging phenotype in SUFU associated with familial medulloblastoma may include hamartomatous skin lesions. Consideration of these features, along with macrocephaly will alert clinicians to the likely genetic basis of the syndrome, affording the opportunity for genetic counselling, prenatal or pre-implantation genetic diagnosis in at-risk families.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2017
DOI: 10.1158/1055-9965.EPI-16-0496
Abstract: Background: People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol consumption and colorectal cancer risk have been inconclusive. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer. Results: Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and & g/day was associated with increased colorectal cancer risk (HR, 1.50 95% CI, 1.09–2.07 and 1.69 95% CI, 1.07–2.65, respectively Ptrend = 0.05), and colon cancer risk (HR, 1.78 95% CI, 1.27–2.49 and 1.94 95% CI, 1.19–3.18, respectively Ptrend = 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of in idual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk. Conclusions: Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (∼2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers. Impact: Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk. Cancer Epidemiol Biomarkers Prev 26(3) 366–75. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2015
Publisher: Wiley
Date: 02-2017
DOI: 10.1111/JGH.13468
Publisher: MDPI AG
Date: 02-07-2019
Abstract: Introduction: Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma for which a cure is usually the therapeutic goal of optimal treatment. Using a large population-based cohort we sought to examine the factors associated with optimal DLBCL treatment and survival. Methods: DLBCL cases were identified through the population-based Victorian Cancer Registry, capturing new diagnoses for two time periods: 2008–2009 and 2012–2013. Treatment was pre-emptively classified as ‘optimal’ or ‘suboptimal’, according to compliance with current treatment guidelines. Univariable and multivariable logistic regression models were fitted to determine factors associated with treatment and survival. Results: Altogether, 1442 DLBCL cases were included. Based on multivariable analysis, delivery of optimal treatment was less likely for those aged ≥80 years (p 0.001), women (p = 0.012), those with medical comorbidity (p 0.001), those treated in a non-metropolitan hospital (p = 0.02) and those who were ex-smokers (p = 0.02). Delivery of optimal treatment increased between 2008–2009 and the 2012–2013 (from 60% to 79%, p 0.001). Delivery of optimal treatment was independently associated with a lower risk of death (hazard ratio (HR) = 0.60 (95% confidence interval (CI) 0.45–0.81), p = 0.001). Conclusion: Delivery of optimal treatment for DLBCL is associated with hospital location and category, highlighting possible demographic variation in treatment patterns. Together with an increase in the proportion of patients receiving optimal treatment in the more recent time period, this suggests that treatment decisions in DLBCL may be subject to non-clinical influences, which may have implications when evaluating equity of treatment access. The positive association with survival emphasizes the importance of delivering optimal treatment in DLBCL.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2019
DOI: 10.1038/S41523-019-0115-9
Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 ( PALB2 ) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2 -associated breast cancers (BCs), and whether PALB2 -associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2 -associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH ( n = 11) or second somatic mutations ( n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2 -associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2 -associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2 -associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
Publisher: Springer Science and Business Media LLC
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 28-03-2014
Publisher: Springer Science and Business Media LLC
Date: 08-2001
Publisher: AMPCo
Date: 07-2013
DOI: 10.5694/MJA13.10381
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000502917
Abstract: The prospect of healthcare systems offering population-based preventive genomic testing to all adults is becoming feasible. Some single-payer or state-funded healthcare systems are already considering offering universal testing as part of routine care. In countries with public healthcare systems, there is a unique opportunity to provide such testing in the form of a national screening program, following existing national population health-screening frameworks. This paradigm, if achievable, could help deliver a degree of testing quality and equity-of-access that may not be possible in private-payer or direct-to-consumer models, to maximize prevention and health benefits. Here, we outline some of the major challenges ahead in considering this prospect and discuss the research that is helping shape the future direction in Australia and elsewhere.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1038/S41598-019-52000-3
Abstract: Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA s les were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein ( AIP ) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of % and precision of %. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
Publisher: Wiley
Date: 04-06-2019
DOI: 10.1002/MGG3.781
Publisher: Wiley
Date: 07-03-2012
DOI: 10.1111/J.1440-0960.2011.00740.X
Abstract: We present a patient with keloid scars and Dupuytren's contracture comprising the polyfibromatosis syndrome four members over three generations of his family are also affected. To our knowledge this is the first familial case reported of polyfibromatosis with this specific phenotypic presentation and probable X-linked recessive inheritance.
Publisher: BMJ
Date: 23-10-2018
Abstract: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder which leads to accumulation of poorly soluble 2,8-dihydroxyadenine in kidneys resulting in nephrolithiasis as well as chronic kidney disease from crystal nephropathy. This report describes a 55-year-old previously fit man who presented with shortness of breath and the investigative pathway that eventually led to a diagnosis of APRT deficiency. Early diagnosis has aided in timely institution of allopurinol, thereby improving his renal function and possibility of weaning off renal replacement therapy. Genetic testing has enabled early identification of other family members at risk and prevention of renal failure by commencing xanthine oxidoreductase (XOR) inhibitors. The issues surrounding kidney donation by a member of this family are also discussed. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition, complications of which can be easily prevented by early institution of XOR inhibitor therapy.
Publisher: S. Karger AG
Date: 2020
DOI: 10.1159/000508963
Abstract: b i Introduction: /i /b Genomic tests can predict risk and tailor screening recommendations for colorectal cancer (CRC). Primary care could be suitable for their widespread implementation. b i Objective: /i /b We aimed to assess the feasibility and acceptability of administering a CRC genomic test in primary care. b i Methods: /i /b Participants aged 45–74 years recruited from 4 Australian general practices were offered a genomic CRC risk test. Participants received brief verbal information about the test comprising 45 CRC-associated single-nucleotide polymorphisms, before choosing whether to undertake the test. Personalized risks were given to testers. Uptake and knowledge of the genomic test, cancer-specific anxiety (Cancer Worry Scale), psychosocial impact (Multidimensional Impact of Cancer Risk Assessment [MICRA] score), and impact on CRC screening behaviour within 6 months were measured. b i Results: /i /b In 150 participants, test uptake was high (126, 84%), with 125 (83%) having good knowledge of the genomic test. Moderate risk participants were impacted more by the test (MICRA mean: 15.9) than average risk participants (mean: 9.5, difference in means: 6.4, 95% confidence interval (CI): 1.5, 11.2, i /i = 0.01), but all scores were low. Average risk participants’ cancer-specific anxiety decreased (mean differences from baseline: 1 month −0.5, 95% CI: −1.0, −0.1, i /i = 0.03 6 months −0.6, 95% CI: −1.0, −0.2, i /i = 0.01). We found limited evidence for genomic testers being more likely to complete the risk-appropriate CRC screening than non-testers (41 vs. 17%, odds ratio = 3.4, 95% CI: 0.6, 34.8, i /i = 0.19), but some mediators of screening behaviour were altered in genomic testers. b i Conclusions: /i /b Genomic testing for CRC risk in primary care is acceptable and likely feasible. Further development of the risk assessment intervention could strengthen the impact on screening behaviour.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2011
DOI: 10.1038/BJC.2011.41
Publisher: Springer Science and Business Media LLC
Date: 15-07-2022
DOI: 10.1186/S13053-022-00233-1
Abstract: A suspected Lynch syndrome (SLS) diagnosis is made when a tumor exhibits DNA mismatch repair deficiency but cannot be definitively assigned to an inherited or non-inherited etiology. This diagnosis poses challenges for healthcare professionals, patients, and their families in managing future cancer risks and clinical care. This qualitative study aimed to explore the psychosocial and behavioral responses of endometrial cancer (EC) patients receiving a SLS diagnosis (EC-SLS). Semi-structured telephone interviews were conducted with 15 EC-SLS women, transcribed, and thematically analyzed. Most who interpreted their result as negative for Lynch syndrome (LS) believed they were at population-level risk of cancer and felt happy and relieved. Many participants who interpreted their result as inconclusive/not definitive for LS were confused about their cancer risk and experienced negative emotions of anger and frustration. Despite variation in colorectal cancer screening recommendations reported by participants, most adhered to the advice given. Almost all participants communicated their genetic test result to immediate family members however, communication of family cancer risk management advice was more limited due to most participants reporting not receiving family screening advice. A family history of cancer and a professional healthcare background influenced participants’ engagement in regular cancer screening. These findings highlight variability in the psychosocial and behavioral responses associated with EC-SLS, providing insight into how healthcare professionals can optimally manage and support such in iduals.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.EJCA.2010.07.041
Abstract: The aim of this prospective cohort study of women attending a rehabilitation course at the Dallund Rehabilitation Centre was to explore the emotional and psychological aspects of living with lymphoedema, expressed as psychological distress, poorer quality of life and poorer self-reported health. Between November 2002 and January 2007 within the FOCARE study, self-completed questionnaires were collected 3 weeks before and 6 and 12 months after the rehabilitation course to elicit sociodemographic, physical and lifestyle information and responses to three psychometric tests. The population consisted of 633 women, 125 with and 508 without verified lymphoedema (time since surgery, 1 month-5 years). The population was reduced to 553 women at the first follow-up and 494 at the second. Multivariate analysis showed that, in comparison with women without lymphoedema, those with lymphoedema had a 14% higher risk for scoring one level higher on the POMS-SF test, a 9% higher probability of scoring one point lower on the quality of life scale and a 29% higher likelihood of reporting poorer or bad health than women without lymphoedema. These findings were seen at all three measurement times. In this cohort of women with breast cancer, women with lymphoedema after surgery for breast cancer had significantly worse overall emotional well-being and adjustment to life compared to women without lymphoedema.
Publisher: BMJ
Date: 24-03-2017
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Publisher: Hindawi Limited
Date: 28-10-2010
DOI: 10.1002/HUMU.21339
Publisher: AMPCo
Date: 11-2013
DOI: 10.5694/MJA13.10978
Publisher: AMPCo
Date: 09-2015
DOI: 10.5694/MJA14.01674
Abstract: To describe patient characteristics, standard operating procedure, and uptake of genetic testing at the multidisciplinary Cardiac Genetics Clinic (CGC) at the Royal Melbourne Hospital during its first 6 years. Database exploration of referral diagnoses, sex, number of clinic visits and incidence of genetic testing in a population of in iduals attending the CGC. Tertiary referral hospital (Royal Melbourne Hospital) providing cardiac genetics services to the state of Victoria. All in iduals initially attending the clinic between July 2007 and July 2013, either as the proband or as an at-risk family member. Classification of patients into diagnostic categories, number of probands and at-risk relatives assessed, incidence and outcomes of genetic testing. 1170 in iduals were seen for the first time over the 6-year period 57.5% made only one visit. The median age was 39 years. Most were encompassed within four broad diagnostic categories: cardiomyopathy (315 patients), aortopathy (303 patients), arrhythmia disorders (203 patients) and resuscitated cardiac arrest and/or family history of sudden cardiac death (341 patients) eight patients had "other" diagnoses. Genetic testing (mutation detection or predictive testing) was undertaken in 381 in iduals (32.6%), and a pathogenic mutation was identified in 47.6% of tests, representing 15.3% of the total population. The CGC fulfils an important role in assisting clinicians and patients by reviewing genetic cardiac diagnoses. Clinical practice during the study period moved from a selected candidate gene approach to broader gene panel-based testing. This move to next-generation sequencing may increase the detection of mutations and variants of unknown significance. A major contribution by the clinic to the care of these in iduals and their families is the provision (or negating) of a diagnosis, and of a plan for managing risks of predictable cardiac disease.
Publisher: Wiley
Date: 14-07-2015
DOI: 10.1002/IJC.29641
Publisher: Oxford University Press (OUP)
Date: 07-12-2005
DOI: 10.1093/NDT/GFI312
Abstract: Alport syndrome (ATS) is a progressive inherited nephropathy characterized by irregular thinning, thickening and splitting of the glomerular basement membrane (GBM) often associated with hearing loss and ocular symptoms. ATS has been shown to be caused by COL4A5 mutations in its X-linked form and by COL4A3 and COL4A4 mutations in its autosomal forms. Five families with a suspicion of ATS were investigated both from a clinical and molecular point of view. COL4A3 and COL4A4 genes were analysed by DHPLC. Automated sequencing was performed to identify the underlying mutation. Molecular analysis indicated that in all 5 cases the correct diagnosis was autosomal recessive ATS. In three families in which parental consanguinity clearly pinpointed to autosomal recessive ATS, we found COL4A4 homozygous mutations in two of them and COL4A3 homozygous mutation in the other one. In the remaining two families a differential diagnosis including X-linked ATS, autosomal recessive ATS and thin basement membrane nephropathy was considered. The molecular analysis demonstrated that the probands were genetic compounds for two different mutations in the COL4A4 gene pinpointing to the correct diagnosis of autosomal recessive ATS. A clinical evaluation of probands and their relatives of the five families carrying mutations in either the COL4A3 or the COL4A4 gene was carried out to underline the natural history of the autosomal recessive ATS. In addition, this paper stresses the complexity of the clinics and genetics of ATS and how a correct diagnosis is based on a combination of: (i) an in-depth clinical investigation (ii) a detailed formal genetic analysis (iii) a correct technical choice of the gene to be investigated (iv) a correct technical choice of the family member to be included in the mutational screening. A correct diagnosis is the basis for an appropriate genetic counselling dealing with both the correct prognosis and the accurate recurrence risk for the patients and family members.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1038/GIM.2017.265
Abstract: The abstract to this article contained errors in the Results and Conclusions section. The corrected sections are shown below.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2013
DOI: 10.1158/1055-9965.EPI-12-1211
Abstract: Background: Previous reports suggest that relatives of colorectal cancer (CRC)-affected probands carrying the BRAF p.V600E mutation are at an increased risk of CRC and extracolonic cancers (ECC). In this study, we estimated the association between a family history of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation. Methods: Population-based CRC cases (probands, ages 18–59 years at diagnosis), recruited irrespective of family cancer history, were characterized for BRAF p.V600E mutation and mismatch repair (MMR) status. ORs and 95% confidence intervals (CI) were estimated using multivariable logistic regression. Results: The 690 eligible probands showed a mean age at CRC diagnosis of 46.9 ± 7.8 years, with 313 (47.9%) reporting a family history of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a family history of CRC than probands that were BRAF wild-type (OR, 0.46 95% CI, 0.24–0.91 P = 0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was greater for those with a CRC-affected first- or second-degree relative (49.3 ± 6.4 years) compared with those without a family history (43.8 ± 10.2 years P = 0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands were to show a family history of CRC (OR, 1.09 per year of age 95% CI, 1.00–1.18 P = 0.04). Conclusions: Probands with early-onset, BRAF-mutated, and MMR-proficient CRC were less likely to have a family history of CRC than probands that were BRAF-wild-type. Impact: These findings provide useful insights for cancer risk assessment in families and suggest that familial or inherited factors are more important in early-onset, BRAF-wild-type CRC. Cancer Epidemiol Biomarkers Prev 22(5) 917–26. ©2013 AACR.
Publisher: Wiley
Date: 09-2015
DOI: 10.1111/AJD.12188
Abstract: A case of halo naevi and café au lait macule regression in a renal transplant patient receiving long-term immunosuppressive therapy is described. We propose the direct transfer of an auto-reactive antibody, CD8 T-cells or tumour necrosis factor α from the transplant donor to the recipient as a possible cause. We have also considered insufficient immunosuppressive therapy as a possible mechanism.
Publisher: Wiley
Date: 11-2018
DOI: 10.1111/IMJ.13953
Abstract: Immunohistochemistry for loss of expression of one or more of the mismatch repair proteins is performed on colorectal cancer tissue as a screening test for Lynch syndrome however, its role in pre-malignant polyps remains controversial. To determine the effectiveness of mismatch repair immunohistochemistry performed on pre-malignant colorectal polyps in identifying Lynch syndrome, focusing on clinical utility and value. A retrospective audit was conducted of mismatch repair immunohistochemistry performed on non-malignant polyps in patients who attended the Family Cancer Clinic at the Royal Melbourne Hospital. Two hundred and six patient records over a 10-year period (2006-2016) were reviewed. Personal and family history data were collected, including genetic testing results. Of the 57 patients who underwent polyp testing, the family histories comprised Amsterdam II Criteria (12.3%), Lynch syndrome-associated malignancies (42.1%), Lynch syndrome-associated malignancies and polyps (35.1%) and polyps only (8.8%) 10.5% of patients had no significant family history. Normal expression of the mismatch repair proteins was observed in 94.7% of patients loss of expression was observed in three in iduals with concordant germline variants in two patients (one PMS2 variant of unknown significance and one MSH6 mutation). Additional genetic testing in 21 patients with normal immunohistochemistry did not identify any additional Lynch syndrome cases. The clinical utility of mismatch repair immunohistochemistry on polyp tissue was low. No additional cases of Lynch syndrome were identified, and a large proportion of patients proceeded to germline testing despite normal polyp immunohistochemistry. We suggest there is no value in this approach.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.HRTHM.2013.08.022
Abstract: It has been reported that cardiological screening and genetic evaluation in relatives of families with sudden unexplained death syndrome and unexplained cardiac arrest (UCA) may uncover a heritable etiology in a significant proportion of families. To evaluate the yield of a comprehensive evaluation protocol of a large unselected cohort of consecutive families with autopsy-negative sudden unexplained death syndrome (termed sudden arrhythmic death syndrome [SADS]) and UCA. We studied (1) 109 consecutive families (411 relatives) referred with 1 or more sudden deaths in the family and (2) 52 consecutive probands with UCA (91 relatives) referred by cardiologists between January 2007 and December 2012. A comprehensive cardiological screening was performed followed by targeted genetic evaluation if a clinical phenotype was proven or suspected. Diagnosis was made by a multidisciplinary team using published clinical criteria. A diagnosis was made in 19 of 109 families with SADS (yield 18%), with the majority having long QT syndrome (LQTS). Diagnosis varied according to proband age, with LQTS most common in the very young (≤20 years) and Brugada syndrome in the older age probands (≥40 years) (P = .03). In contrast, a diagnosis was made in 32 of 52 families with UCA (yield 62%), the majority of which had LQTS and Brugada syndrome. No clinical or circumstantial factors increased the likelihood of diagnosis in families with either SADS or UCA. In contrast to previously published series, a comprehensive strategy of cardiological evaluation and targeted genetic testing in more than 100 families with SADS was found to have a lower diagnostic yield (18%). Diagnostic yield in families with UCA was approximately 4 times higher (62%), which is consistent with the published literature.
Publisher: Wiley
Date: 27-03-2019
DOI: 10.1111/AJD.13033
Publisher: Oxford University Press (OUP)
Date: 16-10-2010
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.FERTNSTERT.2006.03.054
Abstract: FOXO3A and FOXO1A are excellent candidate genes for the development of premature ovarian failure and have not been analyzed previously in POF patients. Potentially causal mutations in FOXO3A (2/90 2.2%) and FOXO1A (1/90 1.1%) were identified in POF patients however, the pathological role of these mutations will be determined only by screening increased numbers of patients and controls, or by functional studies.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 11-09-2014
DOI: 10.1111/CGE.12255
Abstract: When clinicians facilitate and patients make decisions about predictive genetic testing, they often base their choices on the predicted emotional consequences of positive and negative test results. Research from psychology and decision making suggests that such predictions may often be biased. Work on affective forecasting-predicting one's future emotional states-shows that people tend to overestimate the impact of (especially negative) emotional events on their well-being a phenomenon termed the impact bias. In this article, we review the causes and consequences of the impact bias in medical decision making, with a focus on applying such findings to predictive testing in clinical genetics. We also recommend strategies for reducing the impact bias and consider the ethical and practical implications of doing so.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2014
Publisher: Wiley
Date: 07-1985
DOI: 10.1111/J.1399-0004.1985.TB01220.X
Abstract: We have investigated a South African family of Indian stock in which 4 brothers and 2 cousins had a severe form of osteogenesis imperfecta (OI) together with blindness due to hyperplasia of the vitreous, corneal opacity and secondary glaucoma. To the best of our knowledge the syndromic association of OI and ocular problems of this type has not previously been reported, and we believe that this condition is a newly recognised entity. The pedigree is consistent with autosomal recessive inheritance.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.18.00093
Publisher: Springer Science and Business Media LLC
Date: 14-02-2020
Publisher: Oxford University Press (OUP)
Date: 11-2005
Abstract: Inhibin is an important glycoprotein that is involved in folliculogenesis. INHA, the gene encoding the inhibin alpha subunit, was recently proposed as a candidate for premature ovarian failure (POF), a syndrome that leads to the cessation of ovarian function under the age of 40 years. 70 POF patients and 70 controls were screened for the previously identified INHA -16C>T transition mutation. The T allele was found in 31/70 (44.3%) of controls, but only 18/70 (25.7%) of POF patients. This result indicates that the T allele is significantly underrepresented in the POF patient population (Fisher's exact test, two-tail: P = 0.033). Sequence analysis of the INHA promoter in 50 POF patients and 50 controls identified a highly polymorphic imperfect TG repeat at approximately -300 bp, that consisted of four common haplotypes (A, B, C and D). The -16T allele is linked to the shortest repeat haplotype (haplotype C). Despite the association between haplotype C and POF, no significant difference was found between the promoter activity of a luciferase reporter construct containing haplotype C, and most of the other haplotypes tested. Interestingly, haplotype B failed to show any promoter activity. We conclude that the inheritance of specific INHA promoter haplotypes predispose to the development of premature ovarian failure.
Publisher: Elsevier BV
Date: 2020
Publisher: Future Medicine Ltd
Date: 09-2021
Abstract: Aim: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-miRNA signature (MEL38) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign nevi to metastatic melanoma spectrum is examined. Patients & methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin-fixed paraffin-embedded biopsies of nevi, melanoma in situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analyzed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx class V or more advanced) from lower-risk skin lesions (class I–IV) with an area under the curve of 0.97 (p 0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0–IV disease. Using an optimized classification threshold of ≥2.7 accurately identifies higher-risk melanomas with 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to Spitz nevi reveals an intrasubtype profile, with elements in common to both nevi and melanoma. Conclusion: Melanoma-specific circulating miRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The MEL38 signature is an accurate and reproducible metric of melanoma status, based on changes in miRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalized genomic information about their patient’s skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilization and patient outcomes.
Publisher: Oxford University Press (OUP)
Date: 08-03-2021
Abstract: It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P & .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
Publisher: Wiley
Date: 02-09-2015
DOI: 10.1007/S10897-015-9875-Z
Abstract: We present a case where a variant of uncertain significance in the von Hippel Lindau syndrome gene (VHL) was identified in a proband with haemangioblastoma, and in a second degree relative with phaeochromocytoma. Initial uncertainty due to the unclear nature of the variant created psychosocial challenges for this family, in which four other genetic conditions were also present. Subsequent RNA studies confirmed this as a novel pathogenic mutation affecting splicing of exon 2. A third relative has since been diagnosed with haemangioblastoma. We suggest that this mutation possibly has reduced penetrance as there was no history of haemangioblastoma, renal tumours (apart from small cysts) or other VHL tumours among five mutation positive and seven untested adult relatives at 50 % risk of the VHL mutation (average age 46 years, range 18-70 years). This case presents a novel VHL splicing mutation and highlights the psychosocial and medical value of additional laboratory studies on uncertain variants for in iduals, their families and for the health professionals providing advice and counseling.
Publisher: Wiley
Date: 28-08-2020
DOI: 10.1111/AJD.13149
Publisher: Oxford University Press (OUP)
Date: 15-02-2006
Abstract: Premature ovarian failure (POF) is a common condition affecting 1% of women worldwide. There is strong evidence for genetic involvement in POF as many cases are familial, and mutations in several genes have been associated with POF. We investigated variation in FOXE1 polyalanine tract length, following the observation that polyalanine tract deletions are seen in the closely related FOXL2 in patients with POF. In addition, polyalanine tract expansions in FOXL2 are often seen in patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), a rare eyelid disorder often associated with POF. The FOXE1 polyalanine tract shows marked variation in its length between POF patients and normal controls, existing as an allele of 12, 14, 16, 17 or 19 alanine residues. We found evidence to suggest that variation in FOXE1 polyalanine tract length predisposes to POF.
Publisher: Informa UK Limited
Date: 07-2013
DOI: 10.2147/TACG.S34116
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2011
Publisher: Elsevier BV
Date: 05-2013
Publisher: Public Library of Science (PLoS)
Date: 16-08-2018
Publisher: Elsevier BV
Date: 06-2011
Publisher: Public Library of Science (PLoS)
Date: 05-05-2016
Publisher: Wiley
Date: 07-09-2019
DOI: 10.1016/J.JALZ.2019.05.011
Abstract: In iduals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some in iduals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These "resilient" in iduals may carry protective genetic factors. This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small s le sizes and used control populations too young to be clearly defined as controls for LOAD.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 21-06-2002
DOI: 10.1002/AJMG.10459
Abstract: A critical region exists at 5p13 for the phenotype associated with duplication 5p. Two unrelated Polynesian children are reported with supernumerary marker chromosomes (SMCs) 5. This brings to seven the total of reported SMCs derived from chromosome 5. The phenotype is clear, and the level of mosaicism of the marker chromosomes is contributory to the clinical severity.
Publisher: Elsevier BV
Date: 08-2008
Publisher: Oxford University Press (OUP)
Date: 18-07-2020
Abstract: In many countries, population colorectal cancer (CRC) screening is based on age and family history, though more precise risk prediction could better target screening. We examined the impact of a CRC risk prediction model (incorporating age, sex, lifestyle, genomic, and family history factors) to target screening under several feasible screening scenarios. We estimated the model’s predicted CRC risk distribution in the Australian population. Predicted CRC risks were categorized into screening recommendations under 3 proposed scenarios to compare with current recommendations: 1) highly tailored, 2) 3 risk categories, and 3) 4 sex-specific risk categories. Under each scenario, for 35- to 74-year-olds, we calculated the number of CRC screens by immunochemical fecal occult blood testing (iFOBT) and colonoscopy and the proportion of predicted CRCs over 10 years in each screening group. Currently, 1.1% of 35- to 74-year-olds are recommended screening colonoscopy and 56.2% iFOBT, and 5.7% and 83.2% of CRCs over 10 years were predicted to occur in these groups, respectively. For the scenarios, 1) colonoscopy was recommended to 8.1% and iFOBT to 37.5%, with 36.1% and 50.1% of CRCs in each group 2) colonoscopy was recommended to 2.4% and iFOBT to 56.0%, with 13.2% and 76.9% of cancers in each group and 3) colonoscopy was recommended to 5.0% and iFOBT to 54.2%, with 24.5% and 66.5% of cancers in each group. A highly tailored CRC screening scenario results in many fewer screens but more cancers in those unscreened. Category-based scenarios may provide a good balance between number of screens and cancers detected and are simpler to implement.
Publisher: Wiley
Date: 07-03-2017
DOI: 10.1111/AJD.12605
Abstract: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant condition, which manifests as cutaneous leiomyomas (CL), uterine fibroids and renal cell cancer (RCC). We describe the case of a 53-year-old woman who presented with multiple CL with a novel heterozygous canonical splice site mutation in intron 9 of the fumarate hydratase (FH) gene IVS 9-1 G>C (NM_000143.3:c 1391-1 G>C) that was not detected on initial screening of a mutation hotspot but was picked up on sequencing the remaining exons and splice site junctions. This report highlights the importance of clinical suspicion in the diagnosis of HLRCC in the absence of a family or personal history of cancer and despite initial genetic testing being negative.
Publisher: Massachusetts Medical Society
Date: 24-10-2013
DOI: 10.1056/NEJMC1306326
Publisher: Springer Science and Business Media LLC
Date: 16-10-2021
DOI: 10.1186/S13053-021-00201-1
Abstract: A diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis. Semi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services. Participants’ interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants’ interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received. Our study findings highlight the variability in patients’ interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.
Publisher: Informa UK Limited
Date: 31-03-2019
Publisher: Wiley
Date: 30-12-2007
DOI: 10.1111/J.1399-0004.2007.00943.X
Abstract: The delivery of good health care services within clinical settings is predicated by an understanding of the needs of the stakeholders. Most of the information generated to date on the transfer of mutational analysis to clinical service has been within a Eurocentric model favouring in idual autonomy. It is predictable that this model does not easily translate for other cultures. Current genetic technology has elucidated the molecular basis of many diseases. In familial cancer and other late-onset disorders, there is now the possibility of 'prediction' where a high risk conferred by family history can be confirmed or negated by genetic testing. In paediatric disorders, prediction is offered in the form of prenatal or pre-implantation genetic diagnosis. We report on the processes undertaken in an attempt to provide a culturally sensitive service for the Maori people of Aotearoa, New Zealand.
Publisher: Wiley
Date: 09-05-2016
DOI: 10.1002/IJC.30153
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.FERTNSTERT.2006.02.107
Abstract: Mutational screening of the bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) genes in a population with premature ovarian failure (POF) identified no new mutations. However, three single nucleotide polymorphisms in the BMP15 gene, two in the 5' untranslated region (31T>G and 71C>G) and another in exon 1 (387G>A), were found to be common in both POF and control groups.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1038/GIM.2014.5
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2011
Publisher: Springer Science and Business Media LLC
Date: 04-04-2018
DOI: 10.1007/S10689-018-0081-7
Abstract: Hemangioblastomas are rare vascularized central nervous system tumors, which can occur sporadically or be associated with von Hippel Lindau Syndrome. The pathogenesis of hemangioblastomas in von Hippel Lindau Syndrome is proposed to involve a pseudohypoxic intracellular state induced by dysregulation of hypoxia inducible factor alpha due to the absence of von Hippel Lindau protein complex mediated destruction. Dysregulation of fumarate hydratase, a tricarboxylic acid cycle enzyme, occurs in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome due to germline fumarate hydratase gene mutations, and also results in oncogenesis via hypoxia inducible factor alpha dysregulation. We present a case study of hemangioblastoma occurrence in a Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome patient and propose it as possible evidence of a phenotypic overlap between von Hippel Lindau and Hereditary Leiomyomatosis and Renal Cell Cancer Syndromes due to their overlapping role in the biochemical regulation of hypoxia inducible factor alpha.
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2022
DOI: 10.1101/2022.06.20.22276419
Abstract: Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. We assessed tumor features, in idually and in combination, in whole-exome sequenced (WES) colorectal cancers (CRCs) and in panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) for their accuracy in detecting dMMR. CRCs (n=300) with WES, where MMR status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, MSISensor), COSMIC tumor mutational signatures (TMS) and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for 1) in idual features, 2) Lasso statistical model and 3) an additive feature combination approach. Panel sequenced tumors (29 CRCs, 22 ECs, 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided % dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3%. The additive feature approach with ≥3/6 of MSMuTect, MANTIS, MSIseq, MSISensor, INDEL count or TMS ID2+ID7 achieved 99.7% accuracy. For the panel sequenced tumors, the additive feature combination approach of ≥3/6 achieved accuracies of 100%, 95.5% and 100%, for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs, however, an approach combining tumor features may improve dMMR prediction in both WES and panel sequenced data across tissue types.
Publisher: Wiley
Date: 21-03-2013
DOI: 10.1111/J.1440-0960.2011.00875.X
Abstract: The porphyrias are a group of inherited disorders that result in defects in the enzymes of the haem biosynthetic pathway, causing photosensitive bullous skin eruptions or abdominal and neurological attacks. Enzymatic defects result in specific porphyrin excretory patterns that are diagnosed biochemically and can be confirmed by genetic testing. Defects in the coproporphyrinogen oxidase (CPOX) enzyme result in the autosomal dominant hereditary coproporphyria. Multiple mutations have been identified in the CPOX gene and incomplete penetrance is noted. Latent carriers without clinical evidence of disease are at risk of life-threatening attacks. Porphyria cutanea tarda may be inherited, but is more commonly acquired. Occasionally two forms of porphyria may co-exist. The importance of genetic testing is discussed.
Publisher: Wiley
Date: 2003
DOI: 10.1002/PD.587
Abstract: An amniocentesis was performed on a 22-week pregnancy following the detection of foetal abnormalities on ultrasound. A rapid aneuploid screen using fluorescence in situ hybridisation on uncultured amniotic fluid cells revealed 3 signals for chromosome 21, consistent with trisomy 21. In situ metaphase cultures revealed a 46,XY normal male karyotype. These discordant results may be explained by a sub-standard batch of the commercially available probe or alternatively, a very specific variation within the s le interacting with the probe. Alternative strategies are proposed in order to safeguard against inappropriate clinical action as a consequence of discordant results.
Publisher: Wiley
Date: 02-12-2019
DOI: 10.1111/AJD.12958
Abstract: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico-pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist-initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 in iduals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. The 882 in iduals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two-thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282 74.5%). MMR-deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281 66.5%). The highest AUC for discriminating MMR-deficient sebaceous lesions from MMR-proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). The best combination of measured clinico-pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR-deficient sebaceous skin lesions.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.JOCN.2010.04.054
Abstract: Von Hippel-Lindau disease is an inherited syndrome predisposing to a variety of benign and malignant neoplasms of the central nervous system and viscera that requires comprehensive screening and follow-up of in iduals and their families. As such, it is important for the neurosurgeon to be aware of its clinical features and management issues. In this article we review the clinical aspects, management and surveillance of von Hippel-Lindau disease for neurosurgical practice.
Publisher: American College of Physicians
Date: 15-12-2020
DOI: 10.7326/M20-1443
Publisher: AMPCo
Date: 03-2016
DOI: 10.5694/MJA15.01335
Abstract: Inherited predisposition to breast cancer is explained only in part by mutations in the BRCA1 and BRCA2 genes. Most families with an apparent familial clustering of breast cancer who are investigated through Australia's network of genetic services and familial cancer centres do not have mutations in either of these genes. More recently, additional breast cancer predisposition genes, such as PALB2, have been identified. New genetic technology allows a panel of multiple genes to be tested for mutations in a single test. This enables more women and their families to have risk assessment and risk management, in a preventive approach to predictable breast cancer. Predictive testing for a known family-specific mutation in a breast cancer predisposition gene provides personalised risk assessment and evidence-based risk management. Breast cancer predisposition gene panel tests have a greater diagnostic yield than conventional testing of only the BRCA1 and BRCA2 genes. The clinical validity and utility of some of the putative breast cancer predisposition genes is not yet clear. Ethical issues warrant consideration, as multiple gene panel testing has the potential to identify secondary findings not originally sought by the test requested. Multiple gene panel tests may provide an affordable and effective way to investigate the heritability of breast cancer.
Publisher: Wiley
Date: 14-02-2019
DOI: 10.1111/AJD.13007
Location: China
Location: South Africa
No related grants have been discovered for Ingrid Winship.