title: Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families.
abstract: The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL) in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg); MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), TMC1 (c.362+18A>G), BSND (c.97G>C, p.Val33Leu), TMPRSS3 (c.726C>G, p.Cys242Trp) and MSRB3 (c.20T>G, p.Leu7Arg)). Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48%) missense changes, 4 (19%) nonsense mutations, 3 (14%) intronic mutations, 2 (9%) splice site mutations and 2 (9%) frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13%) cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Sobia
authors.initials: S
authors.lastname: Shafique
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
authors.forename: Saima
authors.initials: S
authors.lastname: Siddiqi
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Ayub
authors.affiliation: Simon Fraser University, Vancouver, British Colombia, Canada.
authors.forename: Ammad
authors.initials: A
authors.lastname: Bilal
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Celia Zazo
authors.initials: CZ
authors.lastname: Seco
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
authors.forename: Atika
authors.initials: A
authors.lastname: Mansoor
authors.affiliation: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
authors.forename: Kehkashan
authors.initials: K
authors.lastname: Mazhar
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Syed Tahir A
authors.initials: ST
authors.lastname: Shah
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Alamdar
authors.initials: A
authors.lastname: Hussain
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan; Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
mesh_terms: D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D023281:Genomics; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009218:Myosins / Q000235:genetics; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics; D010154:Pakistan; D010375:Pedigree; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C485245:MYO15A protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000072259:Connexin 26; D012697:Serine Endopeptidases; C409042:TMPRSS3 protein, human; D009218:Myosins