Splice-altering Variant in COL11A1 As a Cause of Nonsyndromic Hearing Loss DFNA37

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2018 Sep 25

PMID 30245514

Citations 24

Authors

Kevin T Booth

James W Askew

Zohreh Talebizadeh

Patrick L M Huygen

James Eudy

Judith Kenyon

Denise Hoover

Michael S Hildebrand

Katherine R Smith

Melanie Bahlo

William J Kimberling

Richard J H Smith

Hela Azaiez

Shelley D Smith

Affiliations

Soon will be listed here.

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.

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