Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

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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, 71 (43.6%) 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.

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Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

D P Kelsell, J Dunlop, H P Stevens … (1997)

Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

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Xueqiu Jian, Eric Boerwinkle, Xiaoming Liu (2014)

In silico tools have been developed to predict variants that may have an impact on pre-mRNA splicing. The major limitation of the application of these tools to basic research and clinical practice is the difficulty in interpreting the output. Most tools only predict potential splice sites given a DNA sequence without measuring splicing signal changes caused by a variant. Another limitation is the lack of large-scale evaluation studies of these tools. We compared eight in silico tools on 2959 single nucleotide variants within splicing consensus regions (scSNVs) using receiver operating characteristic analysis. The Position Weight Matrix model and MaxEntScan outperformed other methods. Two ensemble learning methods, adaptive boosting and random forests, were used to construct models that take advantage of individual methods. Both models further improved prediction, with outputs of directly interpretable prediction scores. We applied our ensemble scores to scSNVs from the Catalogue of Somatic Mutations in Cancer database. Analysis showed that predicted splice-altering scSNVs are enriched in recurrent scSNVs and known cancer genes. We pre-computed our ensemble scores for all potential scSNVs across the human genome, providing a whole genome level resource for identifying splice-altering scSNVs discovered from large-scale sequencing studies.

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Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).

L. Everett, B. Glaser, J Beck … (1997)

Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.

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Author and article information

Journal

Title: Human Mutation

Abbreviated Title: Human Mutation

Publisher: Wiley

ISSN: 10597794

Publication date Created: January 2019

Publication date (Print): January 2019

Publication date (Electronic): November 18 2018

Volume: 40

Issue: 1

Pages: 53-72

Affiliations

[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