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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To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Twopoint and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c. 241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212-2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.

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A consanguineous family with autosomal recessive nonsyndromic hearing impairment (NSHI) was ascertained in Pakistan and displayed significant evidence of linkage to 3q13.31-q22.3. The novel locus (DFNB42) segregating in this kindred, maps to a 21.6 cM region according to a genetic map constructed using data from both the deCode and Marshfield genetic maps. This region of homozygosity is flanked by markers D3S1278 and D3S2453. A maximum multipoint LOD score of 3.72 was obtained at marker D3S4523. DFNB42 represents the third autosomal recessive NSHI locus to map to chromosome 3.