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Robert B. Hufnagel, Bin Guan, Ehsan Ullah, Wendi Liang, Carmen Brewer, Stephen P Daiger, Kari E Branham, Jacque L Duncan; RUSH2A: systematic cohort variant modeling reveals phenotypic correlates. Invest. Ophthalmol. Vis. Sci. 2020;61(7):836.
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© ARVO (1962-2015); The Authors (2016-present)
To standardize variant interpretation for the USH2A gene in the RUSH2A natural history study, a large cohort of patients with USH2A-associated disorders and two reported mutations, variant models were generated to demonstrate disease-enriched alleles and genotype-phenotype correlations.
141 unique variants from 127 probands with USH2A-related Usher syndrome type 2A or nonsyndromic retinitis pigmentosa (RP) were evaluated by standard variant interpretation criteria (American College of Medical Genetics) and compared to public interpretation submissions in ClinVar. Allele frequencies calculated for the RUSH2A cohort were displayed using R and compared to a general population database (gnomAD) by Fisher’s exact test with Bonferroni correction.
Disease-associated USH2A alleles on exon 13 were enriched compared to the general population. 31% of variants did not have a clinical interpretation in ClinVar. Of 74 unique variants present in both the RUSH2A cohort and gnomAD, 40.5% were statistically enriched in the RUSH2A cohort. Enrichment evidence altered clinical variant interpretation for 5.6% of variants. For nonsyndromic RP, missense alleles were predominant, and 6 were statistically enriched compared to syndromic. Truncating alleles were predominant in the Usher syndrome subgroup. Patients with 2 truncating mutations were universally associated with hearing loss, and 4-frequency threshold averages were higher in patients with Usher syndrome and truncating alleles than those with only missense alleles. However, among hemizygous patients, p.Cys759Phe, p.Cys3294Trp, p.3358Tyr, and p.Glu3448Lys were significantly associated with RP rather than Usher syndrome.
RUSH2A has provided clinical variant interpretation for 45 disease-associated USH2A variants not present in public databases. Evidence for statistical enrichment in disease and disorder subgroups provides additional certainty in variant interpretation and can inform diagnosis. Truncating alleles are associated with hearing loss severity in patients with Usher type 2, and analysis of visual parameters is ongoing. Additional cohort-level analyses of gene-specific disorders will further improve clinical variant interpretation for retinal degenerations.
This is a 2020 ARVO Annual Meeting abstract.
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