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When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS)

Journal of Human Genetics volume 65, pages 609–617 (2020)Cite this article

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Abstract

Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype–phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.

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Data availability

The data that support the findings of this study are openly available in Clinvar database at https://www.ncbi.nlm.nih.gov/clinvar/docs/submit/, reference number: SUB5843570.

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Acknowledgements

We are grateful to the patients and families for their valuable collaboration. KTB was supported by NIH/NIGMS grant T32 GM007748.

Funding

This work was supported by the Iran National Science Foundation (INSF) (grant number: 96011200).

Author information

Authors and Affiliations

  1. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Marzieh Mohseni, Mojdeh Akbari, Mojgan Babanejad, Fariba Ardalani, Sanaz Arzhangi, Khadijeh Jalalvand, Nooshin Nikzat, Fatemeh Ghodratpour, Kimia Kahrizi & Hossein Najmabadi

  2. Kariminejad—Najmabadi Pathology & Genetics Center, Tehran, Iran

    Marzieh Mohseni & Hossein Najmabadi

  3. Student Research Committee, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Marzieh Mohseni

  4. Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Kevin T. Booth & Hela Azaiez

  5. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Kevin T. Booth

  6. Shahrood genetic counseling center, Welfare office, Semnan, Iran

    Payman Jamali

  7. Department of Pathology, Medical University, Kordestan, Iran

    Omid Ali Adeli

  8. Genetic Counseling Center, Hamadan University of Medical Science, Hamadan, Iran

    Haleh Habibi

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  1. Marzieh Mohseni
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Correspondence to Hossein Najmabadi.

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Mohseni, M., Akbari, M., Booth, K.T. et al. When transcripts matter: delineating between non-syndromic hearing loss DFNB32 and hearing impairment infertile male syndrome (HIIMS). J Hum Genet 65, 609–617 (2020). https://doi.org/10.1038/s10038-020-0740-z

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