Document Type

Article

Publication Date

4-2019

Identifier

DOI: 10.1038/s41436-018-0285-0; PMCID: PMC6431578

Abstract

PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family.

METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family.

RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing.

CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics

Volume

21

Issue

4

First Page

948

Last Page

954

MeSH Keywords

Adolescent; Adult; Child; Child, Preschool; Collagen Type XI; Deafness; Exome; Female; Genetic Linkage; Genotype; Humans; Infant; Infant, Newborn; Male; Pedigree; Phenotype; Protein Isoforms; Whole Exome Sequencing; Young Adult

Keywords

COL11A1; DFNA37; exome sequencing; nonsyndromic hearing loss; splice-site variant.

Comments

Grant support

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Link: https://www.nature.com/articles/s41436-018-0285-0

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