Genomics for ocular diseases, and impact for diagnosis and therapies

R Jamieson1,3, A Ma1,3, B Nash1,2,3, J Grigg1 and B Bennetts2,3

  1. Eye Genetics Research Group, The Children's Medical Research Institute, University of Sydney, Sydney Children's Hospital Network & Save Sight Institute, Sydney, NSW. Australia
  2. Sydney Genome Diagnostics, Sydney Children's Hospital Network, Westmead, Sydney, NSW. Australia
  3. Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, NSW. Australia

Genetic ocular disorders including the retinal dystrophies (RD) and diseases of the eye anterior segment that lead to glaucoma, are very genetically heterogeneous conditions. They are now responsible for more cases of blindness in the working-age population than diabetes. The significant genetic heterogeneity was a challenge for molecular testing, prior to the availability of next-generation sequencing (NGS) capability for genomic interrogation. We investigated the utility of several genomic strategies in these conditions, including targeted NGS (Illumina TruSeq; TruSight and TruSight One Clinical Exomes; HiSeq 2500), whole exome (Agilent SureSelect; Illumina HiSeq 4000) and whole genome sequencing (Illumina HiSeq X Ten). In a cohort of 46 patients with non-syndromic bilateral congenital cataracts, we achieved a mutation detection rate of 70%, providing new diagnostic or inheritance information in all cases. In 29 probands with ocular anterior segment abnormalities, likely causative mutations were found in 40%. Novel phenotypes were found associated with the anophthalmia gene SOX2, and in three patients with GJA8 mutations. In 36 patient with familial or sporadic RD, we found a mutation detection rate of 64%, after examination of 217 known RD genes. We identified a new phenotypic association of cone-rod dystrophy with NMNAT1 mutations, previously only known to be associated with Leber congenital amaurosis. Genomics provides an extraordinary wealth of new diagnostic information in genetic eye diseases, facilitating unprecedented opportunities for development of therapeutic strategies in these conditions.