Abstract
Genetic variants in GJB2 are the most frequent cause of congenital and childhood hearing loss worldwide. The purpose of this study was to delineate the genetic and phenotypic landscape of GJB2 SNV variants. All possible single-nucleotide substitution variants of the coding region of GJB2 (N = 2043) were manually curated following the ACMG/AMP hearing loss guidelines. As a result, 60 (2.9%), 177 (8.7%), 1499 (73.4%), 301 (14.7%) and 6 (0.3%) of the variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign, respectively. 53% (84/158) of the pathogenic/likely pathogenic missense variants were not present in ClinVar. The second transmembrane domain and the 310 helix were highly enriched for pathogenic missense variants, while the intracellular loops were tolerant to variation. The N-terminal tail and the extracellular loop showed high clustering of variants that are associated with syndromic or dominant non-syndromic hearing loss. In conclusion, our study interpreted all possible single-nucleotide substitution coding variants, characterized novel clinically significant variants in GJB2, and revealed significant genotype–phenotype correlations at this common hearing loss locus. Our work provides a prototype for other genes with similarly high genetic and phenotypic heterogeneity.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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JX, ANAT, and ZP contributed to the study conception and design. Material preparation, data collection and analysis were performed by JX, XS, NS and SR. The first draft of the manuscript was written by JX and XS. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Xiang, J., Sun, X., Song, N. et al. Comprehensive interpretation of single-nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss. Hum Genet 142, 33–43 (2023). https://doi.org/10.1007/s00439-022-02479-0
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DOI: https://doi.org/10.1007/s00439-022-02479-0