Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37

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

doi:10.1038/s41436-018-0285-0

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Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37

Journal article

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Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37

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, …

Genetics in medicine, Vol.21(4), pp.948-954

04/2019

DOI: 10.1038/s41436-018-0285-0

PMCID: PMC6431578

PMID: 30245514

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Abstract

The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. 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. 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.

Phenotype

Deafness - genetics

Humans

Child, Preschool

Deafness - physiopathology

Genotype

Infant

Male

Whole Exome Sequencing

Young Adult

Exome - genetics

Collagen Type XI - genetics

Pedigree

Adolescent

Adult

Female

Child

Infant, Newborn

Genetic Linkage

Protein Isoforms - genetics

Details

Title: Subtitle: Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37
Creators: Kevin T Booth - Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
James W Askew - Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
Zohreh Talebizadeh - Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
Patrick L M Huygen - Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
James Eudy - DNA Microarray and Sequencing Core, University of Nebraska Medical Center, Omaha, NE, USA
Judith Kenyon - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
Denise Hoover - Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
Michael S Hildebrand - Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
Katherine R Smith - The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Melanie Bahlo - Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
William J Kimberling - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
Richard J H Smith - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
Hela Azaiez - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA. hela-azaiez@uiowa.edu
Shelley D Smith - Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA. shelley.smith@unmc.edu
Resource Type: Journal article
Publication Details: Genetics in medicine, Vol.21(4), pp.948-954
DOI: 10.1038/s41436-018-0285-0
PMID: 30245514
PMCID: PMC6431578
NLM abbreviation: Genet Med
ISSN: 1530-0366
eISSN: 1530-0366
Publisher: United States
Grant note: P30 GM110768 / NIGMS NIH HHS R01 DC003544 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS
Language: English
Date published: 04/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006481402771

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