Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome

Abstract

Purposes: We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD. Methods: We designed a retrospective study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated. Results: Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559-2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively. Conclusion: USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.

Keywords: USH; USH2A gene; founder mutations; genetic profile; rp.

FIGURE 1

The prevalence of USH2A-IRD and variant category of 768 distinct USH2A variants. (A) Homozygous or compound heterozygous pathogenic mutations were detected in 218 (16.34%, 218/1,334) patients with USH2A-IRD; (B) 218 genetically solved USH2A-IRD patients, including 190 RP and 28 USH patients; (C) ACMG classification of 768 distinct USH2A variants; (D) Proportion of six types of 768 distinct USH2A sequence variants. P or LP, pathogenic or likely pathogenic; VUS, variants of uncertain significance; B or LB, benign or likely benign.

FIGURE 2

Naturally occurring mutations of USH2A detected in patients with IRD. Blue indicates novel mutations first reported in this study; Red indicates mutations were founder mutations identified in East Asian Populations.

FIGURE 3

The type of variation and the distribution of genotype subgroups. (A) Variation types of 388 alleles in USH2A-related RP patients (n = 190); (B) Variation types of 56 alleles in USH2A-related USH patients (n = 28); (C) Allele ratios of distinct variant types between RP and USH, missense group (244 vs. 17), splice and intron group (75 vs. 18), frameshift group (44 vs. 12), nonsense group (24 vs. 9), inframe group (1 vs. 0); (D) Comparison of variant combinations between RP and USH patients, missense/missense group (75 vs. 1), missense/truncating group (89 vs. 15), and truncating/truncating group (26 vs. 12). χ²test: *p < 0.05; **p < 0.01; ***p < 0.001.