High throughput screening of 51 known causative genes in families with congenital cataract. S. Javadiyan1, J. Craig1, S. Sharma1, K. Lower2, K. Burdon1, 3 1) Ophthalmology , Flinders university, Adelaide, South Australia, Australia; 2) Haematology and Genetic Pathology,Flinders university , Adelaide, South Australia, Australia; 3) Menzies Research Institue, University of Tasmania, Hobart, Tasmania, Australia.

   Congenital cataract is a leading cause of blindness in children. Approximately 200,000 children worldwide are blind from this condition. The incidence in Australia is 2.2 per 10,000 live births. Mutations in genes that encode enzymes, structural proteins, membrane proteins, transcription factors and signalling molecules are associated with hereditary forms of the disease. The overall aim of the study is to describe the spectrum of mutations in known congenital cataract genes and to determine the contribution of each gene to the disease in Australia. We screened 51 reported congenital cataract causing genes in 70 probands of families with congenital cataract. The study adhered to the tenets of the Declaration of Helsinki. Custom Ampliseq libraries were sequenced on the Ion Torrent Personal Genome Machine. Reads were mapped against human genome (hg19) and variants called with the Torrent Suite software. Variants were annotated to dbSNP 137 using Ion Reporter (IR 1.6.2). Variants were prioritised for validation if they were not in public databases or an in-house list of known artefacts and were predicted to be protein changing. The average coverage depth was 1014 x while 89.7 % of target bases were covered at least 100 x. A total of 41 novel variants were detected of which 29 have been validated with Sanger sequencing. Five were sequencing errors and 7 are remaining to be validated. Of the 70 probands sequenced, 41 did not have mutations in selected genes. The remaining 29 had at least one variant passing the filtering criteria out of which 3 were benign or non-segregating mutations. Segregating mutations were identified in 11 families. In addition, low penetrance but likely causative mutations were detected in 6 families and 4 further likely causative variants were identified but families were not available for segregation analysis. We are in the process of validation of further 5 candidate mutations for 5 families. We have identified the genetic cause of congenital cataract in ~ 32 % of cases which suggests that more causative genes are yet to be identified. The observed mutations are present in a range of genes including CRYAA, CRYGS, BFSP2, GJA3, GJA8 and GCNT2. The most commonly mutated gene in our repository is GJA8.

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