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 341A > 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); 341A > G(E114G)]. The spectrum of GJB2 sequence variants in Pakistan may reflect shared origins of hearing impairment alleles within the Indian The elevated frequency of GJB2 alleles in large populations has been attributed to relaxed selection and assortative mating in the past two centuries, i.e. a rapid increase in survival and reproductive fitness and higher rates of intermarriage among the deaf (8). Alternatively, being a carrier might confer a selective advantage for better survival, such as thicker epidermis and greater salt concentration in sweat (9). On the other hand, consanguinity was associated with a decreased risk of hearing impairment (HI) due to GJB2 (10).The Pakistani population has become an important resource for research on ARNSHI due to the availability of large extended pedigrees. In addition, about 60% of marriages are consanguineous, of which 80% are first-cousin unions (11). Here, we describe the allele frequency and spectrum of GJB2 sequence variants in Pakistan using data on families with ARNSHI. Materials and methodsThe study was approved by the Quaid-I-Azam University Institutional Review Board and by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals. Informed consent was obtained from all family members who participated in the study.One hundred and ninety-six unrelated Pakistani families with at least two ARNSHI individuals were ascertained from various regions of Pakistan. Medical and family history and information on pedigree structure were obtained from multiple family members. Puretone audiometry at 2500-8000 Hz was performed for selec...

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