An Australian perspective: Genomics, molecular diagnoses and genotype-phenotype insights in the Inherited Retinal Dystrophies

Abstract

Purpose : 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. This study applied next-generation sequencing (NGS) strategies to an IRD cohort to determine their relative clinical value in an Australian diagnostic laboratory setting.

Methods : In a cohort of 100 patients with familial or sporadic IRD, samples were processed following Illumina TruSight One clinical exome and the TruSeq Nano-DNA 30x whole genome protocols. Libraries generated were sequenced on the Illumina NextSeq 550 or HighSeq X Ten instruments. Variants detected in the 256 IRD genes of interest were filtered and prioritized in silico using population allele frequencies, conservation and pathogenicity prediction scores, with final candidate variants classified according to ACMG guidelines.

Results : Novel and previously reported mutations were identified in several genes including ABCA4, CACNA1F and RPGR, and also in syndromic genes BBS1, USH2A and IFT140. Molecular diagnosis was achieved in 72/100 (72%) families allowing for improved patient management and recurrence risk information. This work also identified novel genotype-phenotype correlations for the gene NMNAT1, while in other cases has facilitated a change in clinical diagnosis. WGS analysis in specific families has led to the identification of intronic variants in a novel vitreoretinopathy gene and other disease genes, which are predicted to affect natural gene splicing.

Conclusions : The application of our NGS strategy has been successful in identifying pathogenic variants in the heterogeneous IRDs, highlighting the clinical value of genomic technologies in highly heterogeneous disease. This work has also led to novel genotype-phenotype correlations, including NMNAT1 mutations associating with cone and cone-rod dystrophy. The successful integration with existing NGS testing processes has resulted in our panel-based approach now being provided as the first clinical service for IRD molecular diagnostics in Australasia.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.