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Abstract
Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP; and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.
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1 Department of Ophthalmology, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia
2 Department of Haematology and Genetic Pathology, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia
3 Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia 6009, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; Department of Surgery, University of Melbourne, Victoria 3010, Australia
4 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; Department of Surgery, University of Melbourne, Victoria 3010, Australia; Department of Ophthalmology, Royal Children’s Hospital, Melbourne, Victoria 3052, Australia
5 Department of Surgery, University of Melbourne, Victoria 3010, Australia; Department of Ophthalmology, Royal Children’s Hospital, Melbourne, Victoria 3052, Australia
6 Ophthalmology Department, Women’s and Children’s Hospital, Adelaide, South Australia 5006, Australia
7 Department of Surgery, University of Melbourne, Victoria 3010, Australia; Ophthalmology Department, Women’s and Children’s Hospital, Adelaide, South Australia 5006, Australia; Department of Paediatrics, University of Melbourne, Victoria 3010, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia
8 Department of Ophthalmology, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia