Genetic Mapping of Candidates of N on-Syndromic Deafness Genes

Abstract

Hearing loss represents an important social and medical phenomenon affecting a significant proportion of the popu lation. Congen ital or childhood-onsd dearncss alTects approximately one in thousand children with the majority of cascs having no associated syndromal features (non-syndromic deafness). /\ genetic caLise is responsible for 60% of cases, most of which display an autosomal recessive mode of inheritance. Non-syndrom ic sensorineural deafness is genetically heterogenous. To date approximately 68 autosomal recessive (DFNB) and 53 autosomal dominant (DFNA) hearing impairment loci have been identified. Out of 68 known DFNB loci, most of the recessively inherited forms of hearing impairment calise a phenotypically itlellliclIl severe In pnlltllilld, pI' ' lil1Hllu l II 'milll:: loss except IWNH2, I>I ,' NBHI I 0,111111 I)FNU 16. In the present study, four Pakistani fami li es (A, B, C, D) with autosomal recessive non-syndromic form of deafness, were ascertained from Azad Jammu and Kashmir, Peshawar and Punjab. Family A has three, Band C have six each, and family 0 has four affected individuals. All the affected individuals were deaf since birth showing prelingual deafness and using sign language for communication. Linkage in the four families was studied by genotyping microsatellite markers corresponding to candidate genes, involved in autosomal recessive non-syndromic deafness phenotypes. In family A, linkage was established with DFNB I locus on chromosome 13q12. DNA sequence analysis of exon 2 of GJB2 gene in affected individual (VI-5) detected a non-sense mutation (W24X). In family B, analysis of genotyped markers showed linkage to two loci, DFNB31 on chromosome 9q32-q34 and DFNB49 on chromosome 5q 12.3-q 14.1, identifying one (or possibly both) as the site of a novel autosomal recessive non-syndromic sensorineural hearing loss gene. In family C linkage was detected with DFNB3 on chromosome 17p11.2. MYOl5A gene was screened for the reported mutations in exons 3, 29, 30, 40, and 43 in affected individual of the family. However, no disease causing mutation was detected, suggesting the presence of a novel mutation in the family. In family D, analysis of the results of the genotyped microsatellite markers located on chromosome 9 and 10, showed that the affected individuals were heterozygous with different combinations of parental alleles thus, excluding family D from linkage to chromosme 9 and 10.