2. Academic Validation
  3. Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37

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

  • Genet Med. 2019 Apr;21(4):948-954. doi: 10.1038/s41436-018-0285-0.
Kevin T Booth 1 2,  James W Askew 3,  Zohreh Talebizadeh 4,  Patrick L M Huygen 5,  James Eudy 6,  Judith Kenyon 1,  Denise Hoover 3,  Michael S Hildebrand 7,  Katherine R Smith 8,  Melanie Bahlo 8 9,  William J Kimberling 1,  Richard J H Smith 1,  Hela Azaiez 10,  Shelley D Smith 11
Affiliations

Affiliations

  • 1 Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA.
  • 2 Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 3 Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA.
  • 4 Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
  • 5 Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
  • 6 DNA Microarray and Sequencing Core, University of Nebraska Medical Center, Omaha, NE, USA.
  • 7 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
  • 8 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 9 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • 10 Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA. [email protected].
  • 11 Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA. [email protected].
PMID: 30245514 DOI: 10.1038/s41436-018-0285-0
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.

Keywords

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

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