Suzanne de Bruijn

105 A RIPOR2 deletion is a frequent cause of adult-onset hearing loss The RIPOR2 variant c.1696_1707del associates with adNSHL in eleven additional families An exome sequencing dataset of 1,544 index cases with (presumed) hereditary HL was evaluated for rare RIPOR2 variants. In these cases, (likely) pathogenic variants in known deafness genes were previously addressed in a clinical diagnostic setting. The c.1696_1707del variant was identified in 10 index cases, all diagnosed with adNSHL ( Figure 2 ). Analysis of a dataset obtained through MIP sequencing of 89 HL-associated genes in 64 index cases with (presumed) adNSHL revealed another subject (V:1, W08-1421; Figure 2 ) with this variant. No other rare RIPOR2 variants (AF ≤0.5%) that met the variant filtering criteria were identified. For 6 of the 11 index cases with the c.1696_1707del RIPOR2 variant, family members were included in the study and segregation analysis was performed ( Figure 2 ). The variant was detected in 39 of 40 affected subjects, but not in subject III:10 of familyW04- 262. As observed in family W97-056, the RIPOR2 variant was also found in unaffected subjects namely III:14 of family W04-262 and III:4 of family W15-0495, aged 49 and 50 years respectively. For all 11 index cases, targeted reanalysis of sequencing data for known adNSHL- associated genes 4 was performed to reveal other (likely) pathogenic variants. No rare variants were identified that both segregated with HL in the family and were classified as (likely) pathogenic in ClinVar 24 ( Table S2 ). The presence of an identical RIPOR2 variant in 12 families of Dutch origin is suggestive for a common ancestor. Indeed, a shared haplotype of ~0.71 Mb, flanking the variant (D6S2439-D6S1281), was observed in the seven families and potentially the five single cases ( Supplementary Results , Figure S3 ). Clinical evaluation of individuals with the c.1696_1707del variant and phenocopies To characterize the HL associated with the c.1696_1707del RIPOR2 variant, 200 affected and unaffected subjects from seven families and five single index cases were evaluated between 1997 and 2018. The RIPOR2 variant was found to be present in 64 of the 200 subjects. Detailed clinical data per individual are provided in Table S3 .