A novel missense mutation in GIPC3 causes sensorineural hearing loss in an Iranian family revealed by targeted next-generation sequencing

Abstract

Background: Recent studies have confirmed the utility of targeted next-generation sequencing (NGS), providing a remarkable opportunity to find variants in known disease genes, especially in genetically heterogeneous disorders such as hearing loss (HL). Methods: After excluding mutations in the most common autosomal recessive non-syndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis, we performed NGS in the proband an Iranian family with ARNSHL. The NimbleGen sequence capture array captures codingsequences (CDSs) and 100 bp of the flanking sequence of 129 common deafness genes (cat# Oto-DA3). NGS was performed on the Illumina HiSeq2000. BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV were applied for Bioinformatics analyses. Data filtering with allele frequencies ( < 5 in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFTscores ( > 0.95) prioritized 1 indel (insertions/deletions) and 3 missense variants in this family. Eventually, Sanger sequencing, segregation pattern, the frequency in 50 healthy matched normal controls, and evolutionary conservation of amino acid residues revealed the pathogenic variant. Results: We identified a novel missenseGIPC3 mutation, c.472G > A (p.Glu158 Lys). The pathogenicity of GIPC3c.472G > A was supported by its absence in the population databases and the healthy-matched controls. Sanger sequencing confirmed co-segregation of the mutation with HL. Conclusions: This study is the first report of the contribution of theGIPC3 gene to HL in the Iranian population. Targeted NGS allows easier detection of mutations in relatively uncommon deafness genes in families with ARNSHL.