title: Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.
abstract: The Pakistani population has become an important resource for research on autosomal recessive non-syndromic hearing impairment (ARNSHI) due to the availability of large extended and highly consanguineous pedigrees. Here is presented the first report on the prevalence of gap junction beta-2 (GJB2) variants in Pakistan. One hundred and ninety-six unrelated Pakistani families with ARNSHI were recruited for a study on the genetics of NSHI. DNA sequencing of the GJB2 coding region was done on two affected individuals per family. Evolutionary conservation and predicted effect on the protein product were studied in order to hypothesize whether or not a variant was potentially deleterious. Homozygous putatively functional GJB2 variants were identified in 6.1% of families. None of the putatively functional GJB2 variants were observed in the compound heterozygous state. The six putatively causative variants noted were 231G > A(W77X), 71G > A(W24X), 167delT, 95G > A(R32H), 358-360delGAG(delE120), and 269T > C(L90P), with 231G > A(W77X) and 71G > A(W24X) being the most common. In addition, five benign polymorphisms, 380G > A(R127H), 457G > A(V153I), 493C > T(R165W), 79G > A(V27I), and 341 A > G(E114G), were identified within this population. In a few individuals, benign polymorphisms were observed to occur on the same haplotype, namely [457G > A(V153I); 493C > T(R165W)] and [79G > A(V27I); 341 A > G(E114G)]. The spectrum of GJB2 sequence variants in Pakistan may reflect shared origins of hearing impairment alleles within the Indian subcontinent. The high degree of consanguinity within Pakistan may have maintained the GJB2 prevalence at a much lower rate than within India and other populations.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: R L P
authors.initials: RL
authors.lastname: Santos
authors.forename: M
authors.initials: M
authors.lastname: Wajid
authors.forename: T L
authors.initials: TL
authors.lastname: Pham
authors.forename: J
authors.initials: J
authors.lastname: Hussan
authors.forename: G
authors.initials: G
authors.lastname: Ali
authors.forename: W
authors.initials: W
authors.lastname: Ahmad
authors.forename: S M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005192:Family Health; D005787:Gene Frequency; D005808:Genes, Recessive; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D017720:Molecular Epidemiology; D009154:Mutation; D010154:Pakistan / Q000453:epidemiology; D011110:Polymorphism, Genetic; D015995:Prevalence
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26