High prevalence of exon-13 variants in USH2A-related retinal dystrophy in Taiwanese population

Abstract Background USH2A is a common disease-causing gene leading to Usher syndrome, which is an autosomal recessive disorder characterized by retinitis pigmentosa, and was shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype–phenotype correlations of USH2A -associated retinal dystrophy in Taiwan. Results In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splice sites, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T > G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T > G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference. Conclusions This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A- related retinitis pigmentosa in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T > G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.