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Sci Rep. 2019 Mar 14;9(1):4583. doi: 10.1038/s41598-019-41068-6.

Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency.

Author information

1
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.
2
Department of Medicine, Physician-Scientist Program, Yonsei University Graduate School of Medicine, Seoul, 03722, Korea.
3
Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.
4
Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.
5
Department of Dermatology, Seoul St. Mary's Hospital, Brain Korea 21 PLUS Project for Medical Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
6
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea. hygee@yuhs.ac.kr.
7
Department of Medicine, Physician-Scientist Program, Yonsei University Graduate School of Medicine, Seoul, 03722, Korea. hygee@yuhs.ac.kr.

Abstract

As the number of genes identified for linkage to hearing loss has been increasing and more public databases have become available, we aimed to systematically evaluate all variants reported for nonsyndromic hearing loss (NSHL) based on their allele frequencies (AFs) in the general population. Among the 3,549 variants in 97 NSHL genes reported as pathogenic/likely pathogenic in ClinVar and HGMD, 1,618 were found in public databases (gnomAD, ExAC, EVS, and 1000G). To evaluate the pathogenicity of these variants, we employed AF thresholds and NSHL-optimized ACMG guidelines. AF thresholds were determined using a high-resolution variant frequency framework and Hardy-Weinberg equilibrium calculation: 0.6% and 0.1% for recessive and dominant genes, respectively. Filtering AFs of variants linked to NSHL were obtained based on AFs reported in gnomAD and ExAC. We found that 48 variants in 23 genes had filtering AFs above the suggested thresholds and assumed that these variants might be benign based on their filtering AFs. 47 variants, except for one notorious high-frequency GJB2 mutation (c.109G > A; p.Val37Ile), were confirmed to be benign/likely benign by the NSHL-optimized ACMG guidelines. The proposed systematic approach will aid in precise evaluation of NSHL variant pathogenicity in the context of filtering AFs, AF thresholds, and NSHL-specific ACMG guidelines, thus improving NSHL diagnostics.

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