Ophthalmology (Eye & Ear Hospital) - Research Publications
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ItemRecurrent mutation in the crystallin alpha A gene associated with inherited paediatric cataract.(Springer Science and Business Media LLC, 2016-02-11)BACKGROUND: Cataract is a major cause of childhood blindness worldwide. The purpose of this study was to determine the genetic cause of paediatric cataract in a South Australian family with a bilateral lamellar paediatric cataract displaying variable phenotypes. CASE PRESENTATION: Fifty-one genes implicated in congenital cataract in human or mouse were sequenced in an affected individual from an Australian (Caucasian) family using a custom Ampliseq library on the Ion Torrent Personal Genome Machine. Reads were mapped against the human genome (hg19) and variants called with the Torrent Suite software. Variants were annotated to dbSNP 137 using Ion Reporter (IR 1.6.2) and were prioritised for validation if they were novel or rare and were predicted to be protein changing. We identified a previously reported oligomerization disrupting mutation, c.62G > A (p.R21Q), in the Crystallin alpha A (CRYAA) gene segregating in this three generation family. No other novel or rare coding mutations were detected in the known cataract genes sequenced. Microsatellite markers were used to compare the haplotypes between the family reported here and a previously published family with the same segregating mutation. Haplotype analysis indicated a potential common ancestry between the two South Australian families with this mutation. The work strengthens the genotype-phenotype correlations between this functional mutation in the crystallin alpha A (CRYAA) gene and paediatric cataract. CONCLUSION: The p.R21Q mutation is the most likely cause of paediatric cataract in this family. The recurrence of this mutation in paediatric cataract families is likely due to a familial relationship.
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ItemAssociation of Open-Angle Glaucoma Loci With Incident Glaucoma in the Blue Mountains Eye Study(ELSEVIER SCIENCE INC, 2015-01)PURPOSE: To determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction. DESIGN: Case-control from within a population-based longitudinal study. METHODS: study population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG. RESULTS: Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = .004, respectively). The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors. CONCLUSIONS: This study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma.
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ItemGenome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy(NATURE PUBLISHING GROUP, 2017-03-30)The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10-8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
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ItemNovel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Ayme-Gripp syndrome)(BIOMED CENTRAL LTD, 2017-05-08)BACKGROUND: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son. METHOD: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother. RESULT: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases. CONCLUSION: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.
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ItemDetermining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2019-07)PURPOSE: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). METHODS: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. RESULTS: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. CONCLUSIONS: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.
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ItemIdentification of novel mutations causing pediatric cataract in Bhutan, Cambodia, and Sri Lanka(WILEY, 2018-07)BACKGROUND: Pediatric cataract is an important cause of blindness and visual impairment in children. A large proportion of pediatric cataracts are inherited, and many genes have been described for this heterogeneous Mendelian disease. Surveys of schools for the blind in Bhutan, Cambodia, and Sri Lanka have identified many children with this condition and we aimed to identify the genetic causes of inherited cataract in these populations. METHODS: We screened, in parallel, 51 causative genes for inherited cataracts in 33 probands by Ampliseq enrichment and sequencing on an Ion Torrent PGM. Rare novel protein coding variants were assessed for segregation in family members, where possible, by Sanger sequencing. RESULTS: We identified 24 rare (frequency <1% in public databases) or novel protein coding variants in 12 probands and confirmed segregation of variants with disease in the extended family where possible. Of these, six are predicted to be the cause of disease in the patient, with four other variants also highly likely to be pathogenic. CONCLUSION: This study found that 20%-30% of patients in these countries have a mutation in a known cataract causing gene, which is considerably lower than the 60%-70% reported in Caucasian cohorts. This suggests that additional cataract genes remain to be discovered in this cohort of Asian pediatric cataract patients.
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ItemPrevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance(PUBLIC LIBRARY SCIENCE, 2018-12-05)PURPOSE: The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma. METHOD: A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined. RESULTS: A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes. CONCLUSION: The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.
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ItemWorking Towards Eye Health Equity for Indigenous Australians with Diabetes(MDPI, 2019-12-02)Type 2 diabetes mellitus (T2DM) poses significant challenges to individuals and broader society, much of which is borne by disadvantaged and marginalised population groups including Indigenous people. The increasing prevalence of T2DM among Indigenous people has meant that rates of diabetes-related complications such as blindness from end-stage diabetic retinopathy (DR) continue to be important health concerns. Australia, a high-income and resource-rich country, continues to struggle to adequately respond to the health needs of its Indigenous people living with T2DM. Trends among Indigenous Australians highlight that the prevalence of DR has almost doubled over two decades, and the prevalence of diabetes-related vision impairment is consistently reported to be higher among Indigenous Australians (5.2%-26.5%) compared to non-Indigenous Australians (1.7%). While Australia has collated reliable estimates of the eye health burden owing to T2DM in its Indigenous population, there is fragmentation of existing data and limited knowledge on the underlying risk factors. Taking a systems approach that investigates the social, environmental, clinical, biological and genetic risk factors, and-importantly-integrates these data, may give valuable insights into the most important determinants contributing to the development of diabetes-related blindness. This knowledge is a crucial initial step to reducing the human and societal impacts of blindness on Indigenous Australians, other priority populations and society at large.
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ItemSingle Dose of Pseudoephedrine Induces Simultaneous Bilateral Acute Angle Closure Crisis(KARGER, 2019)Simultaneous bilateral acute angle closure crisis (AACC) is a sight-threatening ocular emergency. Many "cold and flu" preparations contain compounds with sympathomimetic or anticholinergic qualities that confer a risk of inducing AACC. We present a review of cold and flu preparation-induced AACC, and present a case of simultaneous bilateral AACC triggered by a single oral dose of pseudoephedrine. The challenges facing the clinician in recognizing simultaneous bilateral AACC in the context of an upper respiratory tract infection are addressed. An awareness of this uncommon clinical entity, its pertinent clinical features, risk factors, and the drug classes that may precipitate an attack is critical for the timely diagnosis and management of this ocular emergency. Notably, clinicians must be aware that even a single dose of an implicated medication may trigger an attack of AACC.
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ItemRare, potentially pathogenic variants in 21 keratoconus candidate genes are not enriched in cases in a large Australian cohort of European descent(PUBLIC LIBRARY SCIENCE, 2018-06-20)Many genes have been suggested as candidate genes for keratoconus based on their function, their proximity to associated polymorphisms or due to the identification of putative causative variants within the gene. However, very few of these genes have been assessed for rare variation in keratoconus more broadly. In contrast, VSX1 and SOD1 have been widely assessed, however, the vast majority of studies have been small and the findings conflicting. In a cohort of Australians of European descent, consisting of 385 keratoconus cases and 396 controls, we screened 21 keratoconus candidate genes: BANP, CAST, COL4A3, COL4A4, COL5A1, FOXO1, FNDC3B, HGF, IL1A, IL1B, ILRN, IMMP2L, MPDZ, NFIB, RAB3GAP1, RAD51, RXRA, SLC4A11, SOD1, TF and VSX1. The candidate genes were sequenced in these individuals by either whole exome sequencing or targeted gene sequencing. Variants were filtered to identify rare (minor allele frequency <1%), potentially pathogenic variants. A total of 164 such variants were identified across the two groups with no variants fulfilling these criteria in cases in IL1RN, BANP, IL1B, RAD51 or SOD1. The frequency of variants was compared between cases and controls using chi-square or Fishers' Exact tests for each gene with at least one rare potentially pathogenic variant identified in the case cohort. The number of rare potentially pathogenic variants per gene ranged from three (RXRA) to 102 (MPDZ), however for all genes, there was no difference in the frequency between the cases and controls. We conclude that rare potentially pathogenic variation in the 21 candidate genes assessed do not play a major role in keratoconus susceptibility and pathogenesis.
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