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Genotype-phenotype correlations
Original Article
A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct
  1. Parna Chattaraj1,
  2. Tina Munjal1,
  3. Keiji Honda1,
  4. Nanna D Rendtorff2,3,4,
  5. Jessica S Ratay1,
  6. Julie A Muskett1,
  7. Davide S Risso5,
  8. Isabelle Roux1,
  9. E Michael Gertz6,
  10. Alejandro A Schäffer6,
  11. Thomas B Friedman7,
  12. Robert J Morell8,
  13. Lisbeth Tranebjærg2,3,4,
  14. Andrew J Griffith1
  1. 1 Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), Bethesda, Maryland, USA
  2. 2 Institute of Clinical Medicine, University of Copenhagen, The Panum Institute, Copenhagen, Denmark
  3. 3 Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Rigshospitalet, Copenhagen, Denmark
  4. 4 Department of Clinical Genetics, Rigshospitalet/The Kennedy Center, Glostrup, Denmark
  5. 5 Laboratory of Communication Disorders, NIDCD, Bethesda, Maryland, USA
  6. 6 Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, USA
  7. 7 Laboratory of Molecular Genetics, NIDCD, Bethesda, Maryland, USA
  8. 8 Genomics and Computational Biology Core, NIDCD, Bethesda, Maryland, USA
  1. Correspondence to Dr Andrew J Griffith, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, 35A Convent Drive, Rm. GF-103, Bethesda, MD 20892, USA; griffita{at}nidcd.nih.gov

Abstract

Background Enlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and one-half have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype.

Methods We performed genotype–haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families.

Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten ‘mutation-negative’ chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042).

Conclusions The CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

  • caucasian
  • deafness
  • haplotype
  • hearing loss
  • SLC26A4

https://doi.org/10.1136/jmedgenet-2017-104721

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    Footnotes

    • Contributors PC, TM, KH, NDR, IR and RJM contributed to molecular and functional analyses. PC, TM, KH, DSR and RJM contributed to bioinformatic analyses. JSR, JAM, LT and AJG generated and reviewed clinical data. PC, TM, KH, DSR, EMG, AAS, TBF, RJM and AJG contributed to design of experiments and interpretation of molecular and bioinformatic data. PC, TM, KH, RJM and AJG contributed to the first draft of the manuscript. All authors critically reviewed the manuscript. AJG conceptualised the study.

    • Funding Work in the NIH authors’ laboratories was supported by NIH Intramural Research Program funds Z01-DC000060, Z01-DC-000086, Z01-DC-000046, Z01-DC000039 and Z01-LM000097.

    • Competing interests None declared.

    • Ethics approval Combined Neuroscience Institutional Review Board, National Institutes of Health (NIH), Bethesda, Maryland; Danish Research Ethical Committee (KF 01-108/03, 11-112/04, KF120/03).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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