ORCID Profile
0000-0002-0926-7858
Current Organisation
Royal Brisbane and Women's Hospital
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Publisher: Springer Science and Business Media LLC
Date: 26-08-2015
Publisher: Wiley
Date: 11-09-1995
Abstract: Geleophysic dysplasia is characterized by short stature with short limbs and brachydactyly, a "happy" facial appearance, and joint contractures. Infiltration of heart valves and liver with a mucopolysaccharide-like substance has been demonstrated in some patients. A metabolic pathogenesis is suspected, but has not yet been identified. We report on 3 boys with the condition, 2 of whom are brothers. Serial ultrasound scans were performed on 2 of the cases during pregnancy, but short limbs did not become obvious until after 28 weeks of gestation, making it an uninformative procedure for prenatal diagnosis.
Publisher: Wiley
Date: 11-02-2001
DOI: 10.1046/J.1440-1754.2001.00554.X
Abstract: Alveolar capillary dysplasia (ACD) has been described in conjunction with a number of congenital abnormalities. The case reported here was noted in utero to have duodenal atresia and a partial atrioventricular canal defect and a provisional diagnosis of trisomy 21 was considered. A fetal blood s le showed a normal karyotype. The diagnosis of ACD was made at post-mortem following a neonatal death on the tenth day. This case further highlights the range of congenital abnormalities that may be present in cases of ACD that may mimic other conditions, including trisomy 21, on antenatal scan. However, the absence of congenital anomalies, even in the same family, would not exclude the diagnosis of ACD.
Publisher: Hindawi Limited
Date: 09-2005
DOI: 10.1002/HUMU.9362
Abstract: Townes-Brocks syndrome is an autosomal dominantly inherited disorder, which comprises multiple birth defects including renal, ear, anal, and limb malformations. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator SAL of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved, evenly distributed C2H2 double zinc finger domains. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Most mutations causing TBS are clustered in the N-terminal third of the SALL1 coding region and result in the production of truncated proteins containing only one or none of the C2H2 domains and the N-terminal transcriptional repressor domain of SALL1. Twenty-three SALL1 mutations were reported prior to this work, 22 of which are located in exon 2, 5' of the second double zinc finger-encoding region. Here we present 12 novel mutations in SALL1 associated with Townes-Brocks syndrome in 13 unrelated families. These include three nonsense mutations, three short insertions and six short deletions. Thus the number of SALL1 mutations increases to 35. Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia.
Publisher: American Society for Cell Biology (ASCB)
Date: 2015
Abstract: COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.
Publisher: Wiley
Date: 2001
DOI: 10.1002/1096-8628(20010122)98:3<273::AID-AJMG1081>3.0.CO;2-4
Abstract: Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, small palpebral fissures, Pierre Robin sequence, abnormal ears, nuchal laxity and cardiac defects. We report on a female patient who has some additional findings including an anteriorly placed anus. This anomaly adds to the list of other midline anomalies seen in this syndrome. We compare the findings to those seen in the Opitz BBBG syndrome, a well-defined syndrome of the midline developmental field. Our patient, having a severe manifestation of complicated congenital heart disease, died in the neonatal period, which argues against the likelihood that this is an X-linked disorder with more severe manifestations in males.
Publisher: American Society for Clinical Investigation
Date: 08-04-2013
DOI: 10.1172/JCI66466
Publisher: Wiley
Date: 2004
DOI: 10.1002/AJMG.A.20304
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2001
DOI: 10.1097/00019605-200110000-00004
Abstract: Nine cases of Kabuki syndrome have been identified in Auckland and surrounding regions in the North Island, New Zealand since 1995. All have the characteristic facial dysmorphism and many of the well-described associated anomalies. Some of the abnormalities were unusual including a case with severe congenital mitral stenosis, two cases of eventration of the diaphragm, idiopathic thrombocytopaenic purpura and vitiligo. One child had an Arnold Chiari type 1 malformation and another had epibulbar dermoids, neither of which has previously been reported in this syndrome. There was a wide ersity of ethnic origin, with the syndrome being described in patients from the Pacific Islands for the first time. The cases described emphasize the broad range of associated anomalies found in Kabuki syndrome and further illustrate its presence in all ethnic groups.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2001
DOI: 10.1097/00019605-200110000-00001
Abstract: Two sisters presented at 13 and 15 years-of-age respectively with a history of precocious puberty, short stature, endometriosis and mild mixed hearing loss. They had mild learning difficulties and a number of skeletal features in common. Some of these features were present in their father, suggesting a new autosomal dominant entity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2001
DOI: 10.1097/00019605-200101000-00015
Abstract: A 1-year-old male with branchio-oculo-facial syndrome together with preaxial polydatyly and a white forelock at birth is described. This is only the second case where preaxial polydactyly has been described in branchio-oculo-facial syndrome. In both cases a diagnosis of Waardenburg syndrome had been considered.
Publisher: Wiley
Date: 26-08-2002
DOI: 10.1002/AJMG.10632
Abstract: Setleis syndrome is characterized by cutis aplasia or atrophic skin at the temples, which is said to resemble forceps marks. There may also be a coarse facial appearance, anomalies of the eyelashes and eyebrows, and periorbital puffiness. The mouth has a typical appearance with large lips, inverted "V" contour, and downturned overly defined corners. Patients usually have normal intelligence. Here are presented three cases with features of Setleis syndrome. One is an apparently isolated case the others are father and son. All three have developmental delay. This second family is a further ex le of autosomal dominant inheritance in Setleis syndrome. These patients also suggest that developmental problems may be a more common manifestation than previously described. Two of the patients are the first described of Pacific Island descent.
Publisher: Wiley
Date: 17-01-2008
DOI: 10.1002/AJMG.A.32129
Abstract: We present a case of a male with severe mental retardation, seizure disorder, and absence/hypoplasia of the thumb and great toe nails. This combination of clinical findings has been reported only once previously. We suggest it represents a distinct syndrome. Our case has the additional finding of broad thumbs.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 09-08-2011
DOI: 10.1038/MP.2011.95
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2009
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1086/302330
Abstract: Deletions in the distal region of chromosome 8p (del8p) are associated with congenital heart malformations. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive, impulsive behavior. We studied genotype-phenotype correlations in nine unrelated patients with a de novo del8p, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. With the exception of one large terminal deletion, all deletions were interstitial. In five patients, a commonly deleted region of approximately 6 Mb was present, with breakpoints clustering in the same regions. One patient without a heart defect or microcephaly but with mild mental retardation and characteristic behavior had a smaller deletion within this commonly deleted region. Two patients without a heart defect had a more proximal interstitial deletion that did not overlap with the commonly deleted region. Taken together, these data allowed us to define the critical deletion regions for the major features of a del8p.
Publisher: Mary Ann Liebert Inc
Date: 06-2001
DOI: 10.1089/109065701753145600
Abstract: In iduals affected with Fragile X syndrome are usually characterized at the DNA level by the presence of at least 200 CGG repeats in the 5' untranslated region of the FMR1 gene this number of repeats is defined as a full mutation. Repeats that number 50-200 usually define those with premutations and are termed unaffected carriers. We report here a compound heterozygous female who carried CGG repeats in the FMR1 gene that fall within the premutation and full mutation ranges. The former appears to have been inherited from the father, whereas the latter is an expansion of the premutation carried by the proband's mother. Therefore, the offspring of the proband will carry a significant risk of being affected with Fragile X syndrome, and the paternal uncle and any cousins should be counselled for being at risk for this syndrome.
Publisher: Massachusetts Medical Society
Date: 23-06-2016
Publisher: Wiley
Date: 27-04-2017
DOI: 10.1002/AJMG.A.38121
Abstract: In 2011, heterozygous mutations in the ANKRD11 gene were identified in patients with KBG syndrome. Since then, 100 cases have been described with the expansion of the clinical phenotype. Here we present 18 KBG affected in iduals from 13 unrelated families, 16 with pathogenic mutations in the ANKRD11 gene. Consistent features included intellectual disability, macrodontia, and the characteristic broad forehead with hypertelorism, and a prominent nasal bridge. Common features included hand anomalies, cryptorchidism, and a large number of palate abnormalities. Distinctive findings in this series included malrotation of the abdominal viscera, bilateral inguinal herniae in two patients, basal ganglia calcification and the finding of osteopenia in three patients. Nine novel heterozygous variants were found and the genotype-phenotype correlation was explored. This report highlights the need for thorough examination and investigation of the dental and skeletal systems. The results confirm the specificity of ANKRD11 mutations in KBG and further evidence for this transcription repressor in neural, cardiac, and skeletal development. The description of further cases of KBG syndrome is needed to further delineate this condition, in particular the specific neurological and behavioral phenotype.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2022
DOI: 10.1038/S41467-022-32707-0
Abstract: Globally, there is a recognised need that all populations should be able to access the benefits of genomics and precision medicine. However, achieving this remains constrained by a paucity of data that quantifies access to clinical genomics, particularly amongst Indigenous populations. Using administrative data from clinical genetic health services across three Australian jurisdictions (states/territories), we investigate disparities in the scheduling and attendance of appointments among Aboriginal and/or Torres Strait Islander people, compared to non-Indigenous people. For 14,870 appointments scheduled between 2014–2018, adjusted Multivariate Poisson Regression models revealed that Aboriginal and/or Torres Strait Islander people were scheduled fewer appointments (IRR 0.73 [0.68–0.80], .001) and attended at lower rates (IRR 0.85 [0.78–0.93], .001). Within this population, adults, females, remote residents, and those presenting in relation to cancer or prenatal indications experienced the greatest disparity in access. These results provide important baseline data related to disparities in access to clinical genomics in Australia.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.ANNDIAGPATH.2011.04.003
Abstract: This is the first reported case of a sebaceous adenoma arising within an ovarian mature cystic teratoma in a patient with Muir-Torre syndrome. The pathologic findings and a literature review are presented, including the importance and possible benefits of an early diagnosis of Muir-Torre syndrome. It is proposed that the presence of a sebaceous adenoma in an ovarian cystic teratoma may serve as a useful trigger to consider further history and investigations, with the goal of identifying an important genetic cancer predisposition syndrome.
Publisher: Elsevier BV
Date: 05-2021
Publisher: BMJ
Date: 06-1998
DOI: 10.1136/ADC.78.6.531
Abstract: The frequency of deletions within the survival motor neurone (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in patients with spinal muscular atrophy (SMA), and the impact of this on the diagnosis and prenatal diagnosis of SMA, were investigated by molecular analysis of stored DNA and retrospective review of case notes. In type I SMA, 16 of 17 cases were homozygously deleted for exons 7 and 8 of SMN, 14 of 17 were homozygously deleted for exon 5 of NAIP, and 13 of 17 were deleted for both. In types II and III SMA, seven of nine cases were deleted for exons 7 and 8 of SMN. Deletions of SMN and NAIP occurred in four of nine cases. With one exception, the deletion genotypes of probands, affected siblings, and terminated fetuses were identical. Molecular studies are replacing conventional investigations for SMA and have a high uptake prenatally.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.IJCARD.2011.08.083
Abstract: Health status is an important outcome measure that incorporates multiple dimensions of health, including symptoms, functional status, and psychosocial factors. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. We examined health status in a number of cardiac genetic disease groups compared to the general Australian population. A total of 409 in iduals were assessed. In iduals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy (ARVC)] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT)], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (SF-36). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. Patients with HCM (p<0.001), FDC (p<0.05), and CPVT (p<0.05) were found to have a significantly lower PCS, while patients with LQTS (p<0.01) had a lower MCS. In iduals at risk of HCM (p<0.0001) and genotype positive-phenotype negative HCM patients (p<0.01) both had a higher PCS and utility scores compared to the clinically affected HCM population. In iduals at risk of LQTS had significantly higher PCS than those with a clinical diagnosis of LQTS (p<0.05) and similarly in iduals at risk of FDC had significantly higher PCS than FDC patients (p<0.05). In HCM, female gender (p=0.002), presence of co-morbidities (p<0.0001) and higher NYHA functional class (p<0.0001) were predictors of a lower PCS. Patients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies in such patient groups need to consider health status as an important outcome measure.
Publisher: Springer Science and Business Media LLC
Date: 2023
DOI: 10.1038/S41591-022-02142-1
Abstract: Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.
Publisher: EMBO
Date: 10-03-2015
Abstract: Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy ( DCM ), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide ( AON )‐mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal‐dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient‐specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock‐in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo , indicating RNA ‐based strategies as a potential treatment option for DCM .
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 09-1997
DOI: 10.1038/NG0997-18
Publisher: Public Library of Science (PLoS)
Date: 29-01-2014
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: Wiley
Date: 19-07-2004
Publisher: Wiley
Date: 23-09-2017
DOI: 10.1007/S10897-017-0152-1
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmogenic disease with a high risk of sudden cardiac death. The impact on health-related quality of life (HR-QoL) and psychosocial outcomes is not known. We sought to provide the first description of HR-QoL and psychosocial wellbeing of adults with CPVT, parents of affected children and at-risk relatives. Participants were recruited through the Australian Genetic Heart Disease Registry and invited to complete a cross-sectional survey comprising a number of validated scales and open-ended questions. Thirty-five participants completed surveys (response rate 65%), including 19 with CPVT, 10 unaffected parents of a child with CPVT, and 7 at-risk relatives (one participant considered patient and parent). Young patients <40 years were significantly more likely to report anxiety (p = 0.04), depression (p = 0.03) and posttraumatic stress symptoms (p = 0.02) compared to older CPVT patients. Further, young patients with an implantable cardioverter defibrillator (ICD) reported significantly worse device-related distress (p = 0.04) and shock anxiety (p = 0.003). Patients with a genetic diagnosis had worse psychological adaptation than those patients without a gene result. Parents perceived their affected children to have poor quality of life across all subdomains compared to healthy age-matched children, however quality of life of parents and at-risk relatives was comparable to population norms. Ongoing psychosocial care is required for young people with CPVT. Those with an ICD and/or undergoing genetic testing may require additional support. The challenges of CPVT management should extend beyond the clinical and genetic aspects of care to incorporate greater psychosocial support, and further reinforces the need for a multidisciplinary approach to care.
Publisher: BMJ
Date: 04-03-2009
Abstract: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. By a multiplex ligation dependent probe lification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
Publisher: Wiley
Date: 12-2010
Publisher: AMPCo
Date: 02-2016
DOI: 10.5694/MJA15.01157
Publisher: Hindawi Limited
Date: 02-06-2020
DOI: 10.1002/HUMU.24034
Publisher: Massachusetts Medical Society
Date: 09-06-1994
Publisher: Wiley
Date: 2005
DOI: 10.1002/AJMG.A.30896
Abstract: Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease. Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS. There have previously been no reports of a sibling recurrence of this syndrome. A brother and sister are described with clinical features of MWS, where both have the same truncating mutation in exon 8 of ZFHX1B. As their parents are phenotypically normal and do not have the mutation in lymphocyte-derived DNA, the most likely explanation is germ-line mosaicism.
Publisher: Wiley
Date: 09-05-2016
DOI: 10.1002/AJMG.A.37689
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.HLC.2008.05.603
Abstract: A National Genetic Heart Disease Registry has recently been established, with the aim to enroll every family in Australia with a genetically determined cardiomyopathy or primary arrhythmic disorder. The Registry seeks to further our understanding of the impact and burden of disease in this population increase awareness and provide education to health professionals and families and establish a large cardiac genetic cohort as a resource for approved research studies. The Registry is currently recruiting families with inherited cardiomyopathies (e.g. hypertrophic cardiomyopathy) and primary arrhythmogenic disorders (e.g. long QT syndrome), with scope to expand this in the future. Affected in iduals, as well as their first-degree (at-risk) family members are eligible to enroll. Participants are currently being recruited from cardiac genetics clinics in approved recruitment sites and hope to expand to other Australian centres including general cardiology practice in the future. A significant focus of the Registry is to improve understanding and create awareness of inherited heart diseases, which includes ensuring families are aware of genetic testing options and current clinical screening recommendations for at-risk family members. A Registry Advisory Committee has been established under the NHMRC Guidelines, and includes a representative from each major recruitment centre. This committee approves all decisions relating to the Registry including approval of research studies. A National Genetic Heart Disease Registry will provide a valuable resource to further our knowledge of the clinical and genetic aspects of these diseases. Since most of the current data about the prevalence, natural history and outcomes of genetic heart diseases has emanated from the United States and Europe, characterising these Australian populations will be of significant benefit, allowing for more informed and specific health care planning and resource provision.
Publisher: Wiley
Date: 08-09-2022
DOI: 10.1002/AJMG.A.62963
Abstract: Pathogenic variants in CCDC22 were initially described in 2012 in a large Australian family with intellectual disability and were subsequently noted to cause a phenotype consistent with the previously described Ritscher–Schinzel syndrome (RSS). The phenotypes of the original family were not described in detail and remains limited phenotypic data reported in medical literature. We detail the phenotypes of the original family, including newly diagnosed family members. With these eight phenotypic descriptions, more than triple the number of in iduals for whom detailed clinical information is available. In addition to typical facies, common phenotypic features included intellectual disability, congenital heart disease and posterior fossa malformations, postnatal short stature, ectodermal abnormalities, and digital anomalies as previously described. Spinal curvature and genital anomalies were seen in most patients, while gastrointestinal features and disturbed sleep were also recurrently seen. We propose a possible mechanism linking the familial variant to a diagnosis of sarcoidosis in one in idual. Given the clinical and genetic heterogeneity of RSS, we suggest a dyadic naming convention.
Publisher: Swets & Zeitlinger Publishers
Date: 2002
DOI: 10.1076/OPGE.23.4.253.13880
Abstract: Fanconi anemia or pancytopenia is an autosomal recessive condition presenting with a combination of pancytopenia with a mean age of onset of about eight years, a tendency to leukemia, and congenital anomalies. Although ocular abnormalities have been described, cataracts have not been previously reported. We present a patient with proven Fanconi anemia and cataracts.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2015
DOI: 10.1038/NG.3153
Abstract: Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six in iduals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.
Publisher: Wiley
Date: 19-11-2004
DOI: 10.1002/AJMG.A.30407
Abstract: Opitz syndrome (OS MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip alate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X-linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule-associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype-phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in functionally significant neurologic, LTE, anal, and cardiac abnormalities. Minor anomalies were more prevalent in patients with MID1 mutations compared to those without mutations in this study. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. Most of the anomalies found in the patients of the present study do not correlate with the MID1 mutation type, with the possible exception of LTE malformations. This study demonstrates the wide spectrum of severity and manifestations of OS. It also shows that XLOS patients with MID1 mutations may be less severely affected than indicated in prior reports.
Publisher: BMJ
Date: 10-1998
DOI: 10.1136/ADC.79.4.352
Abstract: Klippel-Feil syndrome (KFS) is defined as a short neck with decreased movement and low posterior hairline. Radiologically, there is a failure of cervical segmentation. Deafness is a well known associated feature and may be of sensorineural, conductive, or mixed type. The audiological assessment of 44 patients with KFS is reported. Thirty five were found to have abnormalities on audiological testing. The presence of other features in these patients, reviews of data from other reports, and the need for further study are discussed.
Publisher: Hindawi Limited
Date: 08-2008
DOI: 10.1002/HUMU.20741
Abstract: Klippel-Feil syndrome (KFS) is a congenital disorder of spinal segmentation distinguished by the bony fusion of anterior/cervical vertebrae. Scoliosis, mirror movements, otolaryngological, kidney, ocular, cranial, limb, and/or digit anomalies are often associated. Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with carpal, tarsal, and vertebral fusions. GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc. GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, ersity, and variability of KFS.
Publisher: Oxford University Press (OUP)
Date: 12-2022
DOI: 10.1111/BJD.21832
Abstract: This study shows that gain-of-function variants in KLHL24 causing EBS and DCM, do not only originate in the start-codon and suggest that any nonsense-inducing variant affecting nucleotides c.4_84 will likely cause the same effect on protein level and a similar potential lethal phenotype.
Publisher: Wiley
Date: 06-11-2016
DOI: 10.1002/AJMG.A.37455
Abstract: Ongoing challenges of clinical assessment of long QT syndrome (LQTS) highlight the importance of genetic testing in the diagnosis of asymptomatic at-risk family members. Effective access, uptake, and communication of genetic testing are critical for comprehensive cascade family screening and prevention of disease complications such as sudden cardiac death. The aim of this study was to describe factors influencing uptake of LQTS genetic testing, including those relating to access and family communication. We show those who access genetic testing are overrepresented by the socioeconomically advantaged, and that although overall family communication is good, there are some important barriers to be addressed. There were 75 participants (aged 18 years or more, with a clinical and/or genetic diagnosis of LQTS response rate 71%) who completed a survey including a number of validated scales demographics and questions about access, uptake, and communication. Mean age of participants was 46 ± 16 years, 20 (27%) were males and 60 (80%) had genetic testing with a causative gene mutation in 42 (70%). Overall uptake of cascade testing within families was 60% after 4 years from proband genetic diagnosis. All participants reported at least one first-degree relative had been informed of their risk, whereas six (10%) reported at least one first-degree relative had not been informed. Those who were anxious or depressed were more likely to perceive barriers to communicating. Genetic testing is a key aspect of care in LQTS families and intervention strategies that aim to improve equity in access and facilitate effective family communication are needed.
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Wiley
Date: 15-04-1995
Abstract: An abnormality in cholesterol synthesis was described recently in the Smith-Lemli-Opitz (SLO) syndrome. Here we describe how the application of this finding has enabled an accurate prenatal diagnosis. We also discuss the possible use of this test in detecting heterozygotes.
Publisher: Wiley
Date: 15-03-2016
Publisher: Springer Science and Business Media LLC
Date: 18-03-2021
DOI: 10.1186/S13023-021-01744-1
Abstract: An identical homozygous missense variant in EIF3F , identified through a large-scale genome-wide sequencing approach, was reported as causative in nine in iduals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F- related neurodevelopmental disorder, we examined independent patients. 21 patients were homozygous and one compound heterozygous for c.694T G .(Phe232Val) in EIF3F . Haplotype analyses in 15 families suggested that c.694T G .(Phe232Val) was a founder variant. All affected in iduals had developmental delays including delayed speech development. About half of the affected in iduals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip alate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the in iduals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous in idual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation. Our study refines the phenotypic and expands the molecular spectrum of EIF3F -related syndromic neurodevelopmental disorder.
Publisher: Wiley
Date: 15-08-2002
DOI: 10.1002/AJMG.10786
Publisher: Springer Science and Business Media LLC
Date: 15-09-2015
Publisher: Informa UK Limited
Date: 30-06-2020
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.HLC.2019.12.005
Abstract: Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular genetic disorder. While our mechanistic understanding has been informed by elegant gene discovery studies that led to the term "disease of the sarcomere", more recent investigations have challenged the single-gene hypothesis. Multimodality imaging has allowed better phenotyping to facilitate early diagnosis, identify treatable phenocopies, and guide management. While HCM remains an important cause of sudden death, recent studies have reported a substantial cumulative burden of heart failure and atrial fibrillation in middle-aged and older in iduals. Nonetheless, improvements in risk stratification have allowed early intervention to transition HCM from being a common cause of sudden death in the young to a treatable chronic disease.
Publisher: BMJ
Date: 1996
DOI: 10.1136/JMG.33.1.82
Abstract: We report two patients with Rubinstein-Taybi syndrome out of a total of 16 tested who have a deletion of the region visualised by the cosmid probe RT1. These results further confirm this as a locus for Rubinstein-Taybi syndrome.
Publisher: Wiley
Date: 16-07-2009
DOI: 10.1002/AJMG.A.32973
Publisher: Wiley
Date: 2009
DOI: 10.1002/AJMG.A.32612
Publisher: Wiley
Date: 19-12-2003
DOI: 10.1002/AJMG.A.10784
Publisher: Hindawi Limited
Date: 2006
DOI: 10.1002/HUMU.9449
Abstract: Mutations in the gene TBX5 cause Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by anterior (i.e., radial ray) upper limb malformations and congenital heart defects and/or cardiac conduction anomalies. The detection rate for TBX5 mutations in HOS patients has been given as 30-35% in most reports. However, a detection rate of 74% was reported when strict clinical inclusion criteria for HOS were applied prior to TBX5 analysis. Still, in a significant proportion of typical HOS cases no mutation can be found within the TBX5 coding region and flanking intronic sequences. One explanation could be that large but submicroscopic deletions of TBX5 could cause HOS, yet only one such TBX5 deletion has been reported to date. We developed a quantitative Real Time PCR strategy to detect large, submicroscopic deletions in TBX5. Using this assay, we screened a total of 102 TBX5 mutation negative patients and discovered two novel intragenic deletions. One deletion of 7756 bp removes exon 6 and a considerable part of the neighboring intronic sequences, and the other of 3695 bp removes exon 9 with the stop codon and the 3'UTR completely as well as a part of the preceding intron 8. We conclude that quantitative Real Time PCR is a reliable method to detect submicroscopic deletions within TBX5. However, such deletions explain only approximately 2% of the TBX5 mutational spectrum in HOS cases. In addition, we also present eight novel TBX5 mutations (three nonsense, one splice mutation, four short deletions) as detected by direct sequencing in 21 families not previously analyzed for mutations.
Publisher: BMJ
Date: 06-2000
DOI: 10.1136/JMG.37.6.458
Publisher: American Association for Cancer Research (AACR)
Date: 10-08-2023
DOI: 10.1158/1940-6207.23929352
Abstract: Supplementary Figure S3: Pearson correlation separated by view and case control status.
Publisher: BMJ
Date: 05-2002
DOI: 10.1136/JMG.39.5.311
Abstract: Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk. NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry. Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p<0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma. The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.
Publisher: Wiley
Date: 2002
DOI: 10.1002/PD.258
Abstract: Prenatal specimens were received from a fetus with abnormalities noted on ultrasound. A supernumerary marker chromosome (SMC) was detected: 47,XY,+mar. Fluorescence in situ hybridisation (FISH) further classified this to be partial tetrasomy for chromosome 14. We compare this finding with other cases of SMC (14) and further classify phenotype with karyotype.
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: Public Library of Science (PLoS)
Date: 27-03-2017
Publisher: BMJ
Date: 05-2001
DOI: 10.1136/JMG.38.5.349
Publisher: Wiley
Date: 22-05-2002
DOI: 10.1002/AJMG.10398
Abstract: PHACE syndrome is the term applied to the association of posterior fossa brain abnormalities, hemangiomas, arterial anomalies in the cranial vasculature, coarctation of the aorta/cardiac defects, and eye abnormalities. An overlap with the sternal malformation/vascular dysplasia association has been described. We report an adult patient with complete manifestations of both conditions. As an adult she has demonstrated resolution of the hemangiomas and only mild intellectual difficulties.
Publisher: BMJ
Date: 09-2001
DOI: 10.1136/JMG.38.9.624
Publisher: Elsevier BV
Date: 07-2021
Publisher: Oxford University Press (OUP)
Date: 14-06-2017
Abstract: Physical activity is associated with improved quality of life. Patients with an implantable cardioverter defibrillator (ICD) face unique clinical and psychological challenges. Factors such as fear of ICD shock may negatively impact on physical activity, while a sense of protection gained from the ICD may instil confidence to be active. We aimed to examine the impact of an ICD on physical activity levels and factors associated with amount of activity. Two cross-sectional studies were conducted. Accelerometer data (seven-day) was collected in March–November 2015 for 63 consecutively recruited hypertrophic cardiomyopathy patients, with or without an ICD, aged ⩾18 years. A survey study was conducted in July–August 2016 of 155 in iduals aged ⩾18 years with an inherited heart disease and an ICD in situ. Based on the International Physical Activity Questionnaire, mean leisure time physical activity was 239 ± 300 min/week with 51% meeting physical activity guidelines. Accelerometry showed that mean moderate–vigorous physical activity was the same for patients with and without an ICD (254 ± 139 min/week versus 300 ± 150 min/week, p=0.23). Nearly half of survey participants ( n=73) said their device made them more confident to exercise. Being anxious about ICD shocks was the only factor associated with not meeting physical activity guidelines. Patients with inherited heart disease adjust differently to their ICD device, and for many it has no impact on physical activity. Discussion regarding the appropriate level of physical activity and potential barriers will ensure best possible outcomes in this unique patient group.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2003
Publisher: Springer Science and Business Media LLC
Date: 11-03-2016
DOI: 10.1038/NCOMMS10961
Abstract: The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2018
Publisher: Wiley
Date: 11-01-2013
DOI: 10.1002/IJC.27978
Abstract: Current evidence suggests poor identification and referral of Lynch syndrome patients. This study evaluated the strategies by which patients with endometrial cancer were referred to genetics services. Data from clinic-based patients with endometrial cancer enrolled through the Australian National Endometrial Cancer population-based research study with detailed family history information were analyzed. The Amsterdam II criteria, the revised Bethesda guidelines, and criteria adapted for this study was assessed using personal/family history information. The percentages of patients referred and who could have been referred to genetics services, and the performance of each criterion for identifying possible mismatch-repair (MMR) gene mutation carriers, based on tumor MMR immunohistochemistry (IHC), were determined. Research data indicated that 236/397(59%) of patients with endometrial cancer had family ersonal history of cancer, including 14 (4%) who fulfilled Amsterdam II criteria. Family history information was noted in the hospital records for only 61(15%) patients, including 7/14 (50%) of patients meeting Amsterdam criteria, and always less extensively than that recorded in the research setting. Only 13 patients (two meeting Amsterdam criteria) were referred for genetic assessment. Of 58 patients with tumor MMR protein-IHC loss, the Amsterdam criteria and Bethesda guidelines identified only three and 34% of these possible germline mutation carriers, respectively. Greater sensitivity (60%) was obtained using a single criterion proposed by our study, ≥2 first-degree or second-degree relatives reporting Lynch cancers. Hospital records indicate poor recognition of family history. Application of research methods show improved identification and may facilitate appropriate referrals of endometrial cancer patients with possible Lynch syndrome.
Publisher: Wiley
Date: 10-2002
DOI: 10.1111/J.0004-8666.2002.00486.X
Abstract: Mosaic trisomy 20 is not an uncommon finding on amniocentesis or CVS. Unlike other mosaic aneuploidies it is a relatively benign abnormality which, along with a lack of long-term follow-up of cases, has led to uncertainty when counselling parents. We aimed to identify known mosaic trisomy 20 pregnancies in New Zealand in the last 10 years and document their outcome. Retrospective database review with prospective clinical follow-up. Cases were identified from the databases of the two clinical genetic services, as well as the four regional cytogenetics laboratories. Medical records were reviewed and where patients were available they were offered follow-up. Fourteen cases were identified (13 on amniocentesis, one on CVS), all with low levels of mosaicism (8-50%). In 12 cases, the children were physically and developmentally normal, with the longest follow-up being 10 years. Minor anomalies were noted in two cases. There were no major malformations noted in any of the cases and where repeat karyotypes were performed on blood or urine cytology these were normal. This series confirms a much lower incidence of phenotypic abnormalities associated with mosaic trisomy 20 compared to other forms of mosaic aneuploidy. Attempts to predict which of these pregnancies will have poor outcomes have not proven to be reliable. We recommend that, if a detailed anatomy scan is normal, parents be counselled that the risk of abnormality is less than 10%. Further tests should be performed only on the basis of a clinical indication.
Publisher: BMJ
Date: 10-2002
Publisher: Hindawi Limited
Date: 29-07-2010
DOI: 10.1002/HUMU.21328
Publisher: BMJ
Date: 29-11-2012
DOI: 10.1136/HEARTJNL-2011-300368
Abstract: Traditional management of families with hypertrophic cardiomyopathy (HCM) involves periodic lifetime clinical screening of family members, an approach that does not identify all gene carriers owing to incomplete penetrance and significant clinical heterogeneity. Limitations in availability and cost have meant genetic testing is not part of routine clinical management for many HCM families. To determine the cost-effectiveness of the addition of genetic testing to HCM family management, compared with clinical screening alone. A probabilistic Markov decision model was used to determine cost per quality-adjusted life-year and cost for each life-year gained when genetic testing is included in the management of Australian families with HCM, compared with the conventional approach of periodic clinical screening alone. The incremental cost-effectiveness ratio (ICER) was $A785 (£510 or €587) per quality-adjusted life-year gained, and $A12 720 (£8261 or €9509) per additional life-year gained making genetic testing a very cost-effective strategy. Sensitivity analyses showed that the cost of proband genetic testing was an important variable. As the cost of proband genetic testing decreased, the ICER decreased and was cost saving when the cost fell below $A248 (£161 or €185). In addition, the mutation identification rate was also important in reducing the overall ICER, although even at the upper limits, the ICER still fell well within accepted willingness to pay bounds. The addition of genetic testing to the management of HCM families is cost-effective in comparison with the conventional approach of regular clinical screening. This has important implications for the evaluation of families with HCM, and suggests that all should have access to specialised cardiac genetic clinics that can offer genetic testing.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2021
DOI: 10.1186/S12939-021-01443-0
Abstract: Aboriginal and Torres Strait Islander people do not enjoy equal access to specialist health services that adequately meet their needs. Clinical genetics services are at the vanguard of realising the health benefits of genomic medicine. As the field continues to expand in clinical utility and implementation, it is critical that Aboriginal and Torres Strait Islander people are able to participate and benefit equally to avoid further widening of the existing health gap. This is the first study to explore barriers to accessing clinical genetics services among Aboriginal and Torres Strait Islander people, which has been acknowledged as a key strategic priority in Australian genomic health policy. A participatory design process engaged a majority-Aboriginal Project Reference Group and Aboriginal End-User Group. 63 semi-structured interviews were conducted with Aboriginal and/or Torres Strait Islander people who had accessed the government-funded clinical genetics service in Western Australia, Queensland or the Northern Territory between 2014 and 2018. The s le included patients, parents and carers. Participants were asked to recount their ‘patient journey’, from referral through to post-appointment and reflect on their perceptions of genetics and its implications for the health of themselves and their families. Analysis tracked chronological service engagement, followed by an inductive thematic approach. Barriers to access and engagement were present at each stage of the patient journey. These included challenges in obtaining a referral, long waiting periods, limited genetic literacy, absence of Aboriginal support services, communication challenges and lack of adequate psychosocial support and follow-up after attendance. Participants’ overall experiences of attending a genetic health service were varied, with positive perceptions tied closely to a diagnosis being achieved. The experience of (and expectation for) recognition of cultural identity and provision of culturally safe care was low among participants. Unaddressed concerns continued to cause significant distress in some people years after their appointment took place. There is significant scope for improving the care provided to Aboriginal and Torres Strait Islander people at clinical genetics services. Immediate attention to minimising logistical barriers, developing relationships with Aboriginal Community Controlled Health Services and providing practical and specific cultural safety training for practitioners is required at the service-level. Our findings strongly support the development of guidelines or policies recognising the collective cultural needs of Aboriginal and Torres Strait Islander people in relation to genomic health care.
Publisher: Wiley
Date: 27-06-2016
DOI: 10.1002/AJMG.A.37803
Abstract: Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder, with 25% of patients having mutations in CCBE1. We identified a family with two brothers presenting with primary lymphedema, and performed exome sequencing to determine the cause of their disease. Analysis of four family members showed that both affected brothers had the same rare compound heterozygous mutations in CCBE1. The presumed paternally inherited NM_133459.3:c.310G>A p.(Asp104Asn), lies adjacent to other known pathogenic CCBE1 mutations, while the maternally inherited NM_133459.3:c.80T>C p.(Leu27Pro) lies in the CCBE1 signal peptide, which has not previously been associated with disease. Functional analysis in a zebrafish model of lymphatic disease showed that both mutations lead to CCBE1 loss of function, confirming the pathogenicity of these variants and expanding the genotypic spectrum of lymphatic disorders. © 2016 Wiley Periodicals, Inc.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-07-1997
Abstract: Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands ( P = 0.012) and feet ( P 0.00005). Affected in iduals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.
Publisher: Wiley
Date: 03-2012
DOI: 10.1002/AJMG.A.35224
Abstract: We report on a child with micrognathia, a short, webbed neck, joint contractures, hypoplastic nipples, and a number of other anomalies. There are striking similarities to a patient reported by [Dinno and Weisskopf (1976) Synd Ident, 4:10-12], and we postulate that this child represents the second patient with this condition.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1038/GIM.2012.47
Abstract: Purpose:A genetic diagnosis is an extremely useful tool in the management and care of families with inherited heart diseases, particularly in allowing clarification of risk status of asymptomatic family members. The psychosocial consequences of genetic testing in this group are poorly understood. This longitudinal pilot study sought to determine changes in health-related quality of life in patients and asymptomatic family members undergoing genetic testing for inherited heart diseases.Methods:In iduals attending two specialized multidisciplinary cardiac genetic clinics in Australia were invited to participate. Patients undergoing proband or predictive genetic testing for an inherited cardiomyopathy or primary arrhythmogenic disorder were eligible. The Medical Outcomes Short Form-36 (version 2) was administered before the genetic result was given, and follow-up surveys were completed 1-3, 6, and 12 months after the result was given.Results:A total of 54 in iduals with hypertrophic cardiomyopathy, familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and long QT syndrome completed baseline and at least one follow-up survey, including 33 probands and 21 asymptomatic relatives. Physical and mental component scores analyzed at baseline and 1-3 months were found to be unchanged in all groups. Furthermore, no significant differences were observed up to 12 months after result.Conclusion:In this longitudinal pilot study, no change in health-related quality of life was observed up to 12 months after the result was given in patients and their asymptomatic family members undergoing genetic testing for an inherited heart disease.Genet Med 2012 advance online publication 3 May 2012.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Wiley
Date: 20-07-2012
DOI: 10.1002/AJMG.A.35501
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.GIM.2021.09.001
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with erse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with s les from ≥2 affected in iduals or heterozygotes and 10 cases with ≥2 biospecimens. PCR licons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long licons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
Publisher: Hindawi Limited
Date: 10-2008
DOI: 10.1002/HUMU.20792
Abstract: Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected in iduals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.
Publisher: BMJ
Date: 10-1995
Publisher: Wiley
Date: 2000
DOI: 10.1002/1096-8628(20001002)94:4<311::AID-AJMG9>3.0.CO;2-U
Abstract: The C syndrome is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome first described in sibs. The inheritance has been assumed to be autosomal recessive. Several authors have commented that the combination of anomalies found in the conditions suggest an underlying chromosomal anomaly and in a few apparent cases chromosome anomalies have been described. Our patient had findings consistent with the C syndrome and a duplication of 3p by use of subtelomere probes. This shows that new cytogenetic techniques continue to be important in defining the underlying cause of MCA/MR conditions.
Publisher: MDPI AG
Date: 28-10-2022
DOI: 10.3390/JPM12111781
Abstract: Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie’s Mission—the Australian Reproductive Genetic Carrier Screening Project. Mackenzie’s Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.
Publisher: Wiley
Date: 11-10-2013
DOI: 10.1002/AJMG.C.31378
Abstract: Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 in iduals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 in iduals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for in iduals with craniosynostosis.
Publisher: Nature Publishing Group
Date: 2016
DOI: 10.5167/UZH-134815
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.EJMG.2021.104315
Abstract: Pathogenic variants in ARX lead to a variety of phenotypes with intellectual disability being a uniform feature. Other features can include severe epilepsy, spasticity, movement disorders, agenesis of the corpus callosum, lissencephaly, hydranencephaly and ambiguous genitalia in males. We present the first report of monozygotic female twins with a de novo ARX pathogenic variant (c.1406_1415del p. Ala469Aspfs*20), predicted to result in a truncated ARX protein missing the important regulatory Aristaless domain. The twins presented with profound developmental delay and seizures, consistent with the known genotype-phenotype correlation. Twin 2's features were significantly more severe. She also developed chorea the first time this movement disorder has been seen in an ARX variant other than an expansion of the first polyalanine tract. Differential X-chromosome inactivation was the most likely explanation for the differing severities but could not be conclusively proven.
Publisher: Oxford University Press (OUP)
Date: 10-1996
Abstract: Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2003
Publisher: Wiley
Date: 24-05-2002
DOI: 10.1002/AJMG.10176
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.GIM.2022.04.021
Abstract: The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders. We conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, s le size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools. A search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate. Next generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2002
DOI: 10.1097/00019605-200207000-00005
Abstract: We describe a child with features of the oculo-ectodermal syndrome, who in addition to the cardinal manifestations of cutis aplasia and epibulbar dermoid had a number of other features. These include laryngomalacia, an anterior anus, microcephaly and significant developmental delay. The parents are of New Zealand Maori ancestry and are related as half first cousins, raising the possibility that this syndrome may be recessively inherited.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2010
Publisher: Hindawi Limited
Date: 07-03-2022
DOI: 10.1002/HUMU.24349
Abstract: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
Publisher: American Thoracic Society
Date: 09-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2006
Publisher: Elsevier BV
Date: 07-2022
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 10-2013
Publisher: Wiley
Date: 09-01-2023
DOI: 10.1002/AJMG.A.63110
Abstract: Biallelic pathogenic variants in RNU4ATAC cause microcephalic osteodysplastic primordial dwarfism type I (MOPD1), Roifman syndrome (RS) and Lowry–Wood syndrome (LWS). These conditions demonstrate significant phenotypic heterogeneity yet have overlapping features. Although historically described as discrete conditions they appear to represent a phenotypic spectrum with clinical features not always aligning with diagnostic categories. Clinical variability and ambiguity in diagnostic criteria exist among each disorder. Here we report an in idual with a novel genotype and phenotype spanning all three disorders, expanding the phenotypic spectrum of RNU4ATAC ‐related spliceosomeopathies.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2021
Location: Malaysia
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Julie McGaughran.