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

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

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	English (US)
Pages (from-to)	948-954
Number of pages	7
Journal	Genetics in Medicine
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/s41436-018-0285-0
State	Published - Apr 1 2019

Keywords

COL11A1
DFNA37
exome sequencing
nonsyndromic hearing loss
splice-site variant

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-018-0285-0

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Booth, K. T., Askew, J. W., Talebizadeh, Z., Huygen, P. L. M., Eudy, J., Kenyon, J., Hoover, D., Hildebrand, M. S., Smith, K. R., Bahlo, M., Kimberling, W. J., Smith, R. J. H., Azaiez, H., & Smith, S. D. (2019). Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genetics in Medicine, 21(4), 948-954. https://doi.org/10.1038/s41436-018-0285-0

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title = "Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37",

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",

author = "Booth, {Kevin T.} and Askew, {James W.} and Zohreh Talebizadeh and Huygen, {Patrick L.M.} and James Eudy and Judith Kenyon and Denise Hoover and Hildebrand, {Michael S.} and Smith, {Katherine R.} and Melanie Bahlo and Kimberling, {William J.} and Smith, {Richard J.H.} and Hela Azaiez and Smith, {Shelley D.}",

note = "Funding Information: We would like to thank all family members reported here for their collaboration in this study. Z.T. also acknowledges the helpful advice of Stefan Stamm (University of Kentucky) in the interpretation of splice-site variants. Funding for this study was provided by the National Institute on Deafness and Other Communication Disorders (NIDCD) R01s DC02942 to S.D.S.; RO1s DC003544, DC002842, and DC012049 to R.J.H.S., and the Omaha Community Foundation (S.D.S.). The UNMC DNA Sequencing Core facility is also supported by P30 GM110768: Core B Sequencing (J.D.E., S.D.S.). Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2019",

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doi = "10.1038/s41436-018-0285-0",

language = "English (US)",

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pages = "948--954",

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TY - JOUR

T1 - Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37

AU - Booth, Kevin T.

AU - Askew, James W.

AU - Talebizadeh, Zohreh

AU - Huygen, Patrick L.M.

AU - Eudy, James

AU - Kenyon, Judith

AU - Hoover, Denise

AU - Hildebrand, Michael S.

AU - Smith, Katherine R.

AU - Bahlo, Melanie

AU - Kimberling, William J.

AU - Smith, Richard J.H.

AU - Azaiez, Hela

AU - Smith, Shelley D.

N1 - Funding Information: We would like to thank all family members reported here for their collaboration in this study. Z.T. also acknowledges the helpful advice of Stefan Stamm (University of Kentucky) in the interpretation of splice-site variants. Funding for this study was provided by the National Institute on Deafness and Other Communication Disorders (NIDCD) R01s DC02942 to S.D.S.; RO1s DC003544, DC002842, and DC012049 to R.J.H.S., and the Omaha Community Foundation (S.D.S.). The UNMC DNA Sequencing Core facility is also supported by P30 GM110768: Core B Sequencing (J.D.E., S.D.S.). Publisher Copyright: © 2018, American College of Medical Genetics and Genomics.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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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KW - DFNA37

KW - exome sequencing

KW - nonsyndromic hearing loss

KW - splice-site variant

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ER -

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

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