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Biallelic mutations in pakistani families with autosomal recessive prelingual nonsyndromic hearing loss

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Abstract

Background

Nonsyndromic autosomal recessive hearing loss (DFNB) is an etiologically heterogeneous disorder group showing a wide spectrum of onset ages and severity. DFNB genes are very diverse in their types and functions, making molecular diagnosis difficult. DFNB is particularly frequent in Pakistan, which may be partly due to consanguinity.

Objective

This study was performed to determine the genetic causes in Pakistani DFNB families with prelingual onset and to establish genotype-phenotype correlation.

Methods

Whole exome sequencing and subsequent genetic analysis were performed for 11 Pakistani DFNB families including eight consanguineous families.

Results

We identified eight pathogenic or likely pathogenic mutations in LOXHD1, GJB2, SLC26A4, MYO15A, and TMC1 from six families. The GJB2 mutations were identified in two families each with compound heterozygous mutations and a homozygous mutation. The compound heterozygous mutations in LOXHD1 ([p.D278Y] + [p.D1219E]) and GJB2 [p.M1?] + [p.G12Vfs*2]) were novel. The four missense or start-loss mutations were located at well conserved residues, and most in silico analysis predicted their pathogenicity. In addition to causative mutations, we found compound heterozygous mutations in PTPRQ as variants of uncertain significance.

Conclusion

This study identified biallelic mutations as the underlying cause of early onset DFNB in six Pakistani families. This study will be helpful in providing an exact molecular diagnosis and treatment of prelingual onset deafness patients.

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Data availability

All raw genetic data generated during this study are available upon request to the corresponding author.

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Acknowledgements

This research was supported by grants from the National Research Foundation (2019R1A2C1087547 and 2021R1A4A2001389), Republic of Korea.

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Authors and Affiliations

  1. Department of Biological Sciences, Kongju National University, 56 Gongjudaehak-ro, Gongju, 32588, Korea

    Hee Ji Choi, Nasrin Tamanna, Wonseok Son & Ki Wha Chung

  2. Department of Biosciences, COMSATS University Islamabad, Sahiwal, Pakistan

    Sumaira Kanwal

  3. DHQ Hospital Okara, Tehsil Road, Okara, Pakistan

    Rashid Hameed

  4. Department of Zoology, The Women University Multan, Multan, Punjab, Pakistan

    Shazia Perveen & Hina Mahreen

  5. Department of Physics Education, Kongju National University, 56 Gongjudaehak-ro, Gongju, 32588, Korea

    Kyung Suk Lee

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  1. Hee Ji Choi
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  2. Sumaira Kanwal
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  9. Ki Wha Chung
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Contributions

Chung KW planned and supervised this study. Kanwal S, Hameed R, Perveen S, and Mahreen H collected HL family samples and clinical information. Choi HJ, Kanwal S, and Tamanna N performed the molecular genetic work. Choi HJ, Son W, Lee KS, and Chung KW interpreted the genetic data and conducted the statistical analyses. Son W, and Chung KW wrote the manuscript. All the co-authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Ki Wha Chung.

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Conflict of interest

Choi HJ, Kanwal S, Hameed R, Tamanna N, Perveen S, Mahreen H, Son W, Lee KS, and Chung KW declare that they have no conflict of interest.

Ethics approval and consent to participate

All participants provided written informed consent according to the Declaration of Helsinki. For minors under the age of 18 years, written consent was provided by their parents. This study was approved by the Institutional Review Board of Kongju National University (KNU_IRB_2018-62).

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HJ Choi and S Kanwal contributed equally to this work.

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Choi, H.J., Kanwal, S., Hameed, R. et al. Biallelic mutations in pakistani families with autosomal recessive prelingual nonsyndromic hearing loss. Genes Genom 45, 145–156 (2023). https://doi.org/10.1007/s13258-022-01349-3

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