Japan Whole Exome Project for Inherited Retinal Disease

Abstract

Purpose: We describe the clinical and genetic characteristics of a large cohort with inherited retinal diseases in Japanese population.

Methods: A cohort of 808 subjects from 496 Japanese families with inherited retinal diseases was ascertained between 2008 and 2013. The clinical diagnosis was performed with comprehensive ophthalmic examinations at 12 institutes throughout the nation; then the clinical data were uploaded to the National Institute of Sensory Organs (NISO) databank. The cohort included retinitis pigmentosa (RP; 208 families), occult macular dystrophy (OMD; 64 families), Leber congenital amaurosis (LCA; 23 families), cone (-rod) dystrophy (42 families), macular dystrophy (34 families), Stargardt disease (34 families), congenital stationary night blindness (17 families), and others. Genetic screening and molecular analysis was performed in 387 subjects from 159 families; whole exome sequencing was applied in 147 families and targeted direct sequencing (for RP1L1 or CNGA1) in 12.

Results: Disease-associated mutations were detected in 71/159 (45%) families, including previously reported mutations in 29/159 (18%), novel mutations of previously reported genes in 32/159 (20%), and mutations of putative new associated genes never reported in inherited retinal disease in 10/159 (6%). No definitive disease-associated variants were found in 88/159 (55%) families. Previously reported mutations were detected in 9/61 (15%) of RP, 11/36 (31%) of OMD, and 3/13 (23%) of LCA. Novel mutations of previously reported genes were identified in 13/61 (36%) of RP, 6/36 (17%) of OMD, and 5/13 (38%) of LCA. Putative new genes were associated in 5/61 (8%) of RP and 3/13 (23%) of LCA.

Conclusions: Conclusive molecular genetic diagnosis was obtained in 45% of this Japanese cohort, like other cohorts including autosomal dominant and X-linked disorders in European/American population. Novel mutations of previously reported genes or putative new associated genes were frequently revealed compared to other population, which suggests the distinctive genetic background of Japanese population in inherited retinal diseases.