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Huynh E.,Australian Inherited Retinal Disease Register and DNA Bank | Huynh E.,University of Western Australia | de Roach J.,Australian Inherited Retinal Disease Register and DNA Bank | McLaren T.,Australian Inherited Retinal Disease Register and DNA Bank | And 5 more authors.
Australasian Physical and Engineering Sciences in Medicine | Year: 2016

The assignment of pathogenicity to variants suspected of causing an inherited retinal disease and the subsequent creation of molecular genetic reports sent to clinical geneticists and ophthalmologists has traditionally been time-consuming and subject to error and ambiguity. The purpose of this paper is to describe a computer-assisted method we have developed for (1) assessment of the predicted pathogenicity of genetic variants identified in patients diagnosed with an inherited retinal disease and (2) the incorporation of these results into the Australian Inherited Retinal Disease Register and DNA Bank’s databases, for the production of molecular genetics reports. This method has significantly accelerated the assessment of variant pathogenicity prediction and subsequent patient report generation for the Australian Inherited Retinal Disease Register and DNA Bank, and has reduced the potential for human error. The principles described in this paper may be applied in any situation where genetic variants and patient information are stored in a well-organised database. © 2015 Australasian College of Physical Scientists and Engineers in Medicine Source


Paterson R.L.,Australian Inherited Retinal Disease Register and DNA Bank | De Roach J.N.,Australian Inherited Retinal Disease Register and DNA Bank | McLaren T.L.,Australian Inherited Retinal Disease Register and DNA Bank | Hewitt A.W.,University of Western Australia | And 2 more authors.
Molecular Vision | Year: 2012

Purpose: Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, costeffective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. Methods: DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Results: Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). Conclusions: This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual. © 2012 Molecular Vision. Source


De Roach J.N.,Australian Inherited Retinal Disease Register and DNA Bank | Mclaren T.L.,Australian Inherited Retinal Disease Register and DNA Bank | Paterson R.L.,Australian Inherited Retinal Disease Register and DNA Bank | O'Brien E.C.,Australian Inherited Retinal Disease Register and DNA Bank | And 5 more authors.
Clinical and Experimental Ophthalmology | Year: 2013

Inherited retinal disease represents a significant cause of blindness and visual morbidity worldwide. With the development of emerging molecular technologies, accessible and well-governed repositories of data characterising inherited retinal disease patients is becoming increasingly important. This manuscript introduces such a repository. Design: Participants were recruited from the Retina Australia membership, through the Royal Australian and New Zealand College of Ophthalmologists, and by recruitment of suitable patients attending the Sir Charles Gairdner Hospital visual electrophysiology clinic. Participants: Four thousand one hundred ninety-three participants were recruited. All participants were members of families in which the proband was diagnosed with an inherited retinal disease (excluding age-related macular degeneration). Methods: Clinical and family information was collected by interview with the participant and by examination of medical records. In 2001, we began collecting DNA from Western Australian participants. In 2009 this activity was extended Australia-wide. Genetic analysis results were stored in the register as they were obtained. Main Outcome Measures: The main outcome measurement was the number of DNA samples (with associated phenotypic information) collected from Australian inherited retinal disease-affected families. Results: DNA was obtained from 2873 participants. Retinitis pigmentosa, Stargardt disease and Usher syndrome participants comprised 61.0%, 9.9% and 6.4% of the register, respectively. Conclusions: This resource is a valuable tool for investigating the aetiology of inherited retinal diseases. As new molecular technologies are translated into clinical applications, this well-governed repository of clinical and genetic information will become increasingly relevant for tasks such as identifying candidates for gene-specific clinical trials. © 2012 The Authors Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists. Source


Staffieri S.E.,University of Melbourne | Rose L.,Macquarie University | Chang A.,University of Sydney | De Roach J.N.,Australian Inherited Retinal Disease Register and DNA Bank | And 8 more authors.
Clinical and Experimental Ophthalmology | Year: 2015

Background: X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Design: Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family. Participants: Consanguineous Eastern European-Australian family Methods: Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Main Outcome Measures: Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. Results: By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C>T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous. Conclusion: Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans. © 2015 Royal Australian and New Zealand College of Ophthalmologists. Source


Chiang J.P.-W.,Oregon Health And Science University | Lamey T.,Australian Inherited Retinal Disease Register and DNA Bank | McLaren T.,Australian Inherited Retinal Disease Register and DNA Bank | Thompson J.A.,Australian Inherited Retinal Disease Register and DNA Bank | And 2 more authors.
Expert Review of Molecular Diagnostics | Year: 2015

Next-generation sequencing, also known as massively paralleled sequencing, offers an unprecedented opportunity to study disease mechanisms of inherited retinal dystrophies: a dramatic change from a few years ago. The specific involvement of the retina and the manageable number of genes to sequence make inherited retinal dystrophies an attractive model to study genotype-phenotype correlations. Costs are reducing rapidly and the current overall mutation detection rate of approximately 60% offers real potential for personalized medicine and treatments. This report addresses the challenges ahead, which include: better understanding of the mutation mechanisms of syndromic genes in apparent non-syndromic patients; finding mutations in patients who have tested negative or inconclusive; better variant calling, especially for intronic and synonymous variants; more precise genotype-phenotype correlations and making genetic testing more broadly accessible. © 2015 © The Author(s). Published by Taylor & Francis. Source

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