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Hum Mutat. 2019 Jan;40(1):53-72. doi: 10.1002/humu.23666. Epub 2018 Nov 18.

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.

Author information

1
Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland.
2
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
3
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
4
National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
5
Pakistan Institute of Medical Sciences, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
6
Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
7
Department of Genome Sciences, University of Washington, Seattle, Washington.
8
The Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
9
Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
10
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
11
Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.

Abstract

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

KEYWORDS:

DFNB; Pakistan; allelic heterogeneity; autosomal recessive hearing loss; deafness; genetic spectrum; pathogenic variant

PMID:
30303587
DOI:
10.1002/humu.23666

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