A Comparative Evaluation of the Genetic Variant Spectrum in the USH2A Gene in Russian Patients with Isolated and Syndromic Forms of Retinitis Pigmentosa

Pathogenic variants in the <i>USH2A</i> gene are the primary cause of both non-syndromic autosomal recessive inherited retinitis pigmentosa (RP) and the syndromic form, characterized by retinal degeneration and sensorineural hearing loss. This study presents a comparative assessment of the genetic variant spectrum in the <i>USH2A</i> gene among Russian patients in two clinical groups. A retrospective analysis was conducted on massive parallel panel sequencing data from 2415 blood samples of unrelated patients suspected of having hereditary retinal diseases. The copy number of <i>USH2A</i> exons was determined using the quantitative MLPA method with the MRC-Holland SALSA MLPA kit. Biallelic pathogenic and likely pathogenic variants in the <i>USH2A</i> gene were identified in 69 patients (8.7%). In the group of patients with isolated hereditary RP (55 patients), the most frequent pathogenic variants were p.(Glu4445_Ser4449delinsAspLeu) (20.9%), p.(Trp3955*) (15.5%), and p.(Cys934Trp) (5.5%). In patients with the syndromic form (14 patients), the most frequent variants were p.(Trp3955*) (35.7%) and c.8682-9A>G (17.9%). It was found that patients with isolated vision impairment rarely had two "null" variants (17.8%), whereas this was common among patients with both hearing and vision impairment (71.4%) (<i>p</i> ≤ 0.05), explaining the severity of the disease and the earlier onset of clinical symptoms in the syndromic form of RP. Ten previously undescribed loss-of-function variants were identified. The estimated prevalence of <i>USH2A</i>-associated retinal dystrophy in Russia was 1.9 per 100,000 individuals. The obtained data on the differences in the spectra of genetic variants in the <i>USH2A</i> gene in the two studied groups highlight the importance of establishing genotype-phenotype correlations and predicting disease severity, aiming at potential early cochlear implantation and selection of target therapy.