ORCID Profile
0000-0003-2341-2932
Current Organisations
Royal Melbourne Hospital
,
Royal Australasian College of Physicians
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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: Springer Science and Business Media LLC
Date: 29-06-2020
DOI: 10.1186/S40478-020-00975-W
Abstract: Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G A p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5) . Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.
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: Elsevier BV
Date: 06-2017
Publisher: Wiley
Date: 28-03-2021
DOI: 10.1002/GPS.5535
Abstract: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics. We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases. In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia. Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.
Publisher: Wiley
Date: 02-2021
DOI: 10.1111/IMJ.15185
Publisher: Elsevier BV
Date: 09-2019
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: 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: BMJ
Date: 29-07-2022
Abstract: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer’s disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to th percentile risk. WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.
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: 2021
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 03-2016
DOI: 10.1002/ANA.24595
Abstract: Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected in iduals and reduce frataxin expression. Remaining in iduals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA. We compared clinical information from 111 compound heterozygotes and 131 in iduals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups (2) null (no frataxin produced) (3) moderate/strong impact and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses. Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups. In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA.
Publisher: BMJ
Date: 21-04-2018
No related grants have been discovered for Aamira Huq.