Genomics delivering molecular diagnosis in the complex Inherited Retinal Dystrophies

Benjamin M Nash1,2,3,4, Dale Wright2,4, Bruce Bennetts2,4, John Grigg1,3,4, Robyn V Jamieson1,3,4

1 Eye Genetics Research Unit, Children’s Medical Research Institute, Sydney Children’s Hospital Network, Hawkesbury Rd, Westmead, NSW 2145 Australia
2 Sydney Genome Diagnostics, Sydney Children’s Hospital Network, Hawkesbury Rd, Westmead, NSW 2145 Australia
3 Save Sight Institute, Macquarie St, Sydney, NSW 2000 Australia
4 Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW 2000 Australia

Genomic approaches to genetic diagnosis are proving to be of great value in conditions with high clinical and genetic heterogeneity. The inherited retinal dystrophies (IRD) affect approximately 1/3500 people worldwide and are degenerative disorders of the retina affecting both rod and cone photoreceptors. Prioritising the >250 known causative disease genes is challenging. Until recently, there was no clinical diagnostic testing available for IRD in Australasia allowing for the examination of all the known genes in a cost-effective and timely manner. We are using a combination of next-generation sequencing (NGS) strategies in IRD patients to determine their relative clinical value. In a cohort of 50 patients with familial or sporadic IRD, we have utilised the Illumina TruSight One clinical exome panel. Libraries generated were subsequently sequenced on the NextSeq 550. Variants detected in the 217 RD genes of interest were filtered and prioritised on in silico allele frequencies, conservation and pathogenicity prediction scores, with final candidate variants categorised using ACMG guidelines. Novel and previously reported frameshift, missense and premature stop mutations were identified in several genes including the syndromic genes BBS1, USH2A and IFT140. Molecular diagnosis was achieved in 38/50 (76%) families allowing for improved patient management and recurrence risk information. Our panel-based testing has identified novel genotype-phenotype correlations for the gene NMNAT1, while in other cases has facilitated a change in initial clinical diagnosis to a syndromic form or other type of IRD. The application of our NGS strategy has been successful in identifying pathogenic variants in the heterogeneous IRDs, highlighting the high clinical value of genomic technologies in highly heterogeneous disease. The successful integration with existing NGS testing processes has resulted in our panel-based approach now being provided as a clinical service.


Ben has been working in the field of diagnostic genomics for 10 years, having gained experience across various aspects of cytogenetics and molecular genetics. He is currently in his final year of a part-time Masters by research with the University of Sydney where he is applying next generation sequencing technologies to the blinding retinal dystrophies.

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