A survey of genotypes associated with Leber congenital amaurosis and early-onset severe retinal degeneration identified in a Singaporean patient cohort.

Abstract

Purpose: Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are inherited retinal diseases (IRDs) characterized by visual impairment beginning in infancy or childhood. This study aimed to describe the clinical and genetic characteristics of the first prospectively enrolled Singaporean patient cohort with disease-causing variants in genes associated with LCA, EOSRD, or related early-onset phenotypes.

Methods: Thirty-four patients from 30 families were prospectively recruited and underwent comprehensive clinical and genetic evaluation. Phenotypic classification and genotypic distribution were analyzed and compared with previously reported cohorts.

Results: Of the 34 patients, 24 presented with typical phenotypes of LCA (n = 12) or EOSRD (n = 11). Among the remaining cases carrying genotypes usually linked to LCA, 7 were diagnosed with retinitis pigmentosa, 3 with cone dystrophy, and 1 with macular dystrophy. The most frequently implicated gene was CRB1, detected in 8 families (26.7%), followed by RDH12 (16.7%), and CEP290 and NMNAT1 (10% each). This genetic distribution differs from those reported in Western populations. Clinical phenotypes were heterogeneous with respect to disease course, macular involvement, retinal structural alterations, and residual photoreceptor function.

Conclusions: This study represents the first report of a genetically confirmed cohort of LCA and EOSRD patients from Southeast Asia. The findings highlight a distinct genotypic spectrum compared with Western populations and underscore the extensive clinical heterogeneity of early-onset IRDs. These data provide a valuable foundation for patient stratification and planning of future gene therapy trials in the region.