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Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications

European Journal of Human Genetics volume 30, pages 7–12 (2022)Cite this article

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Abstract

Hearing loss (HL) is one of the most common sensory defects, of which X-linked nonsyndromic hearing loss (NSHL) accounts for only 1–2%. While a COL4A6 variant has been reported in a single Hungarian family with NSHL associated with inner ear malformation, causative role of COL4A6 variants and their phenotypic consequences in NSHL remain elusive. Here we report two families in which we identified a male member with X-linked HL. Each has inherited a rare hemizygous COL4A6 variant from their respective mothers, NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951 + 1 G > C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15, strongly suggesting a pathogenic role for this variant in the HL phenotype. The p.Gly1091Ala variant is classified as a variant of unknown significance based on the variant interpretation guidelines. This report provides evidence for variants in the COL4A6 gene resulting in X-linked NSHL. It highlights the importance of in-depth genetic studies in all family members in addition to the proband, especially in multiplex families, to determine the precise etiology of HL.

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Fig. 1: Two families with COL4A6 variants and sanger sequencing trace for COL4A6.
Fig. 2: Schematic of splicing assay for the COL4A6 c.951 + 1G > T variant identified in Family A.

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Acknowledgements

This study was supported by NIH Grant R01DC009645 from the National Institutes of Health/National Institute on Deafness and Other Communication Disorders.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Genetics and Metabolism, UNC Chapel Hill, Chapel Hill, NC, USA

    Alexander O’Brien & Arti Pandya

  2. UNC Catalyst For Rare Diseases, UNC Eshelman School of Pharmacy, UNC Chapel Hill, Chapel Hill, NC, USA

    Wen Yih Aw, Hui Yi Tee & Kaleb M. Naegeli

  3. Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA

    Guney Bademci & Mustafa Tekin

  4. Emeritus, Department of Science, Technology, & Mathematics, Gallaudet University, Washington, DC, USA

    Kathleen Arnos

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  1. Alexander O’Brien
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Correspondence to Arti Pandya.

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O’Brien, A., Aw, W.Y., Tee, H.Y. et al. Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications. Eur J Hum Genet 30, 7–12 (2022). https://doi.org/10.1038/s41431-021-00881-2

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