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Title: Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.
Austin Authors: Booth, Kevin T;Askew, James W;Talebizadeh, Zohreh;Huygen, Patrick L M;Eudy, James;Kenyon, Judith;Hoover, Denise;Hildebrand, Michael S ;Smith, Katherine R;Bahlo, Melanie;Kimberling, William J;Smith, Richard J H;Azaiez, Hela;Smith, Shelley D
Affiliation: Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
DNA Microarray and Sequencing Core, University of Nebraska Medical Center, Omaha, NE, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Issue Date: 2019 2018-09-24
Publication information: Genetics in medicine : official journal of the American College of Medical Genetics 2019; 21(4): 948-954
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.
DOI: 10.1038/s41436-018-0285-0
ORCID: 0000-0003-2739-0515
PubMed URL: 30245514
Type: Journal Article
Subjects: COL11A1
exome sequencing
nonsyndromic hearing loss
splice-site variant
Appears in Collections:Journal articles

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