Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

Abstract

USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype–phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP.

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

“…Third, truncating alleles are also associated with vision loss in USH2 patients, with earlier onset of and more severe retinal degeneration compared to ARRP (Inaba et al, 2020;Meng et al, 2020;Pierrache et al, 2016). However, we found that the impact of truncating alleles on retinal degeneration may be dependent on clinical diagnosis, as we found no differences in visual symptom onset or severity in those with and without truncating variants in the USH2 and ARRP subgroups.…”

“…Second, in the RUSH2A cohort, hearing loss severity in USH2 is directly related to the number of truncating alleles, as similarly noted by Hartel et al (2016) and Molina‐Ramirez et al (2020), as well as the RUSH2A study (Iannaccone et al, 2021). Third, truncating alleles are also associated with vision loss in USH2 patients, with earlier onset of and more severe retinal degeneration compared to ARRP (Inaba et al, 2020; Meng et al, 2020; Pierrache et al, 2016). However, we found that the impact of truncating alleles on retinal degeneration may be dependent on clinical diagnosis, as we found no differences in visual symptom onset or severity in those with and without truncating variants in the USH2 and ARRP subgroups.…”

“…Multiple studies from different countries have recognized a USH2A allelic hierarchy, where truncating alleles are associated with the clinical diagnosis of USH2 and hearing loss, and several missense alleles are associated with a clinical diagnosis of ARRP (Gao et al, 2021; Hartel et al, 2016; Inaba et al, 2020; Lenassi et al, 2015; Meng et al, 2020; Molina‐Ramirez et al, 2020; Pierrache et al, 2016). The presence of specific missense alleles enriched in ARRP is associated with differences in age of onset and severity of retinal degeneration.…”

“…Presumed truncating alleles, including nonsense, frameshift, and canonical splice variants, have been more frequently associated with hearing loss and, therefore, syndromic disease. Biallelic truncating variants are associated with more severe hearing loss (Hartel et al, 2016; Inaba et al, 2020; Meng et al, 2020; Pierrache et al, 2016). Notably, while earlier onset of visual impairment was noted in patients with USH2, the role of truncating variants has not been clearly established as a risk factor for severe visual impairment.…”

Ocular biometry with swept-source optical coherence tomography-based optical biometer in Japanese patients with EYS-related retinitis pigmentosa: a retrospective study

“…Genetic testing was performed by stepwise Sanger-sequencing using one or two panels of 15 and 27 genes in 2008–2015 [ 13 ] or next-generation sequencing using panels of 39 or 50 genes in 2015–2019 [ 17 ] or 2019 and later [ 18 ], respectively. The patients in this study underwent one of these screenings for genetic diagnosis tests.…”