Identification and computational analysis of USH1C , and SLC26A4 variants in Pakistani families with prelingual hearing
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Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss Muhammad Noman1 · Shazia A. Bukhari1 · Sakina Rehman3 · Muhammad Qasim2 · Muhammad Ali4 · Saima Riazuddin3 · Zubair M. Ahmed3 Received: 2 October 2020 / Accepted: 16 November 2020 © Springer Nature B.V. 2020
Abstract Hearing loss (HL) is clinically and genetically heterogeneous disorder and is the most frequent occurring sensory deficit in humans. This study was conducted to decipher the genetic cause of HL occurring in two large consanguineous Pakistani families (GCNF-01, GCNF-03). Family history and pure tone audiometry of both families suggested prelingual HL, while the affected individuals of GCNF-01 also had low vision and balance problems, consistent with cardinal features of Usher syndrome type I (USH1). Exome sequencing followed by segregating analysis revealed a novel splice site variant (c.8771G > A) of USH1C occurring with USH1 phenotype in family GCNF01. While the affected individual of family GCNF-03 were homozygous for the c.716 T > A, p.(Val239Asp) previously reported pathogenic variant of SLC26A4. Both variants have very low frequencies in control database. In silico mutagenesis and 3-dimensional simulation analyses revealed that both variants have deleterious impact on the proteins folding and secondary structures. Our study expands the mutation spectrum of the HL genes and emphasizes the utility of exome sequencing coupled with bioinformatics tools for clinical genetic diagnosis, prognosis, and family counseling. Keywords Sensorineural hearing loss · USH1C · Usher syndrome · Exome sequencing · Genetic heterogeneity · SLC26A4 · Prelingual hearing impairment
Introduction Hearing play a vital role in our cognitive, speech and social development. Hearing loss (HL) is the most recurrent sensory disability in humans with frequency rate of 1–2:1000 babies, and targeting 360 million people of different ages worldwide [1, 2]. Perception of sound signal requires specialized complex inner ear structures, including support cells, hair cells, stria vascularis, and neurons of spiral * Shazia A. Bukhari [email protected] 1
Department of Biochemistry, Government College University, Faisalabad 38000, Pakistan
2
Department of Biotechnology, Government College University, Faisalabad 38000, Pakistan
3
Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
4
Department of Animal Sciences, Quaid Azam University, Islamabad 46000, Pakistan
ganglion [3]. Several factors including genetic and environmental exposure contribute to the clinical heterogeneity of HL. Genetically, HL can be inherited through several patterns, however, non-syndromic autosomal recessive (NSAR) HL accounts 80%, while the dominant and X-linked HL are only 10–20% of all HL [4]. Populations with high rate of consanguineous marriages and isolated based on geographically, religiously, cultural and social aspects
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