identification of genes and mutations in 10 iranian families with nsarhl by whole exome sequencing

introduction: with prevalence figures close to 0.2% at birth, hearing loss (hl) is the most frequent sensory impairment in childhood. in developed countries, genetic causes account for more than 60% of congenital hl, most often resulting in non-syndromic deafness, which is usually autosomal recessive. hereditary nonsyndromic hearing loss (nshl) in iran is highly heterogeneous, rendering molecular diagnosis difficult. whole-exome sequencing (wes) has recently opened a new page in mendelian disease gene discovery – enabling to study autosomal recessive hl in a new way. the aim of this study is to find more causative genes and their mutations for nsarhl in ten iranian families by wes.  materials and methods: after dna extraction and ruling out for prevalent mutations related to nsarhl in iranian population, the proband of each family has been subjected to wes. each individual was captured with the agilent sureselect human all exon kit, sequenced on the illumina hiseq 2000, and the resulting data processed and annotated with burrows-wheeler aligner (bwa), genome analysis toolkit (gatk), and annovar.   normative population databases (eg, 1000 genomes snp database, dbsnp, and hapmap) were used for comparison. the pathogenicity of variants was predicated using bioinformatics software such as sift, polyphen, conseq, cadd, grpee, dbnsfp and so on. candidate pathogenetic variants have been co-segregate in families using sanger sequencing.  result & discussion: a homozygous missense mutation in slc26a4 and a novel mutation in ptprq genes identified in two families and confirmed by sanger sequencing. data analysis revealed a novel stop codon mutation in myo7a gene in a family but co- segregation analysis failed to confirm this variant as the only cause of hearing loss in this family. further clinical examination showed that the phenotypic variations in family exist and therefore involvement of 2 different genes causing both syndromic and non-syndromic hearing loss is possible. in addition, two novel candidate genes resulting hearing loss have been identified in two families. further studies for confirmation of the pathogenecity of these variations and data analysis of remaining families are under investigation.