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Genotype-phenotype correlations
Original article
Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment
  1. Kevin T Booth1,2,
  2. Kimia Kahrizi3,
  3. Hossein Najmabadi3,
  4. Hela Azaiez1,
  5. Richard JH Smith1,2
  1. 1 Molecular Otolaryngology Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, Iowa, USA
  2. 2 The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
  3. 3 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Islamic Republic of Iran
  1. Correspondence to Dr Hela Azaiez and Professor Richard JH Smith, Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology- Head and Neck Surgery, University of Iowa, Iowa City IA 52242, USA; hela-azaiez{at}uiowa.edu, richard-smith{at}uiowa.edu

Abstract

Background Hearing loss is a genetically and phenotypically heterogeneous disorder.

Objectives The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families.

Methods We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays.

Results We identified two homozygous splice-altering variants (c.37G>T and c.662–1G>C) in the CEACAM16 gene, segregating with the deafness in each family. The minigene splicing results revealed the c.37G>T results in complete skipping of exon 2 and loss of the AUG start site. The c.662–1G>C activates a cryptic splice site inside exon 5 resulting in a shift in the mRNA reading frame.

Conclusions These results suggest that loss-of-function mutations in CEACAM16 result in postlingual progressive hearing impairment and further support the role of CEACAM16 in auditory function.

  • deafness
  • ceacam16
  • non-syndromic hearing loss
  • splice-site

https://doi.org/10.1136/jmedgenet-2018-105349

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    Footnotes

    • KTB and KK contributed equally.

    • HA and RJHS contributed equally.

    • Contributors KTB, KK and HA: conception and study design; designed and performed experiments; gathered and analysed data; and wrote initial manuscript draft and critically read and revised manuscript. HN: study design, gathered clinical data and samples and critically read and revised manuscript. RJHS: conception and study design and critically read and revised manuscript. All authors have approved the finalised manuscript.

    • Funding This study was funded by Iranian National Science Foundation (INSF) grant number: 950100 to KK and NIDCDR01s DC003544, DC002842 and DC012049 to RJS.

    • Competing interests None declared.

    • Patient consent Parental/guardian consent obtained.

    • Ethics approval All procedures were approved by the human research Institutional Review Boards at the Iran University of Medical Sciences and the Welfare Science and Rehabilitation University, Tehran (Iran), and the University of Iowa, Iowa City, Iowa (USA).

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