Genetic analysis of congenital stationary night blindness and Oguchi disease in an Indian cohort.

Background: Congenital stationary night blindness (CSNB) is a group of genetically and clinically heterogeneous non-progressive retinal disorders and can be classified based on fundus abnormalities as found in Oguchi disease or fundus albipunctatus (FA) or based on the absence of severe fundus abnormalities but altered electroretinography (ERG) findings. Here, we report the clinical and genetic findings of 46 CSNB families, with 18 families showing fundus abnormalities and 28 families without fundus abnormalities but having an altered ERG, showing complete CSNB (cCSNB) and Riggs type CSNB.

Methodology: Ophthalmic examinations including full-field ERG recordings, colour vision test, optical coherence tomography and fundus autofluorescence were performed and candidate genes for CSNB were screened by panel-based next-generation sequencing using an Illumina MiSeq platform. Subsequently, Sanger sequencing was performed to validate the identified variants and to confirm segregation with the phenotype in available family members.

Results: In 69% (11/16) of the Oguchi patients', pathogenic variants were found in SAG and GRK1, with p.(R292*) and p.(D537Vfs*7) variants being the most frequent mutations identified in this cohort in the two genes, respectively. A likely pathogenic variant p.(G238A) in RDH5 was identified in one of the two FA patients. In 92% of the CSNB (26/28) families without fundus abnormalities, pathogenic variants were found in NYX, leading to X-linked cCSNB; in GRM6, TRPM1, GPR179, LRIT3, leading to autosomal recessive cCSNB and in GNAT1, leading to autosomal recessive Riggs type CSNB. No significant copy number variants were identified.

Conclusion: Combing this study with our previous report on CSNB from India, the most prevalent gene defects were variants in TRPM1 (37%) followed by GRM6 (32%) > NYX (10%) > SLC24A1 (5%) > GPR179 (5%), GNAT1 (3%) and LRIT3 (3%). In the current study, which included Oguchi disease and FA families as well, variants in SAG (38%) and GRK1 (31%) were identified in the Oguchi disease cases, and in the RDH5 gene in one of the two (50%) FA cases. Unsolved 8/56 (14%) (combined cohorts) cases may harbour variants in novel genes or intronic variants or structural variants undetectable by the screening method used herein.