Comprehensive genetic testing with ethnic‐specific filtering by allele frequency in a Japanese hearing‐loss population

Abstract

Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

“…We focused on the pathogenicity of each CDH23 allele, which were determined by their ethnic-specific MAF in our composite cohort (adult control cohort) (S1 Fig) [24, 25]. …”

“…CDH23 variants were not detected in the 200 normal control chromosomes (< 0.005) from our institute, which was a proposed ethnicity-specific MAF with a cut-off threshold (0.005) for autosomal recessive pathogenic variants [24, 25]. …”

Navigating genetic diagnostics in patients with hearing loss

“…CNV analysis of MPS data has resulted in the identification of several novel CNVs [23*, 25, 31, 32*, 49, 54*] and has shown that many genes can harbor CNVs. Comprehensive CNV detection is as important as comprehensive SNV detection and analysis and must be included in all analytic pipelines.…”

“…Moteki and colleagues diagnosed 27% of 194 probands in a GJB2 -negative Japanese cohort. Their diagnoses included 20 genes and they estimated a diagnostic rate of 40% if they had not preselected their patient population [25]. They also provided an in-depth phenotypic analysis that adds to our knowledge of the clinical presentation associated with several genes, including LRTOMT, P2RX2, POU3F4, PTPRQ , and USH2A [26–30].…”

“…With respect to the former, Moteki et al and Sloan-Heggen et al showed that a positive family history for autosomal dominant NSHL or ARNSHL versus sporadic hearing loss is associated with diagnostic rates of 35% (Moteki, autosomal dominant), 35% (Moteki, AR) and 19% (Moteki, sporadic), and 50% (Sloan-Heggen, AD), 41% (Sloan-Heggen, AR) and 37% (Sloan-Heggen, sporadic), respectively [23,25]. …”