A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type Ⅱ

Waardenburg syndrome typeⅡ(WS2) is associated with syndromic deafness.A subset of WS2,WS2A,accounting for approximately 15%of patients,is attributed to mutations in the microphthalmia-associated transcription factor(MITF) gene.We examined the genetic basis of WS2 in a large Chinese family.All 9 exons of the MITF gene,the single coding exon(exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA(mtDNA) 12S rRNA were sequenced.A novel heterozygous mutation c.[74243delAAinsT;74647delCA]in exon 8 of the MITF gene co-segregates with WS2 in the family.The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids.The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+ [235delC]compound heterozygous pathogenic mutation in the GJB2 gene.No pathogenic mutation was found in mtDNA 12S rRNA in this family.Thus,a novel compound heterozygous mutation,c.[74243delAAinsT;74647delCA]in MITF exon 8 was the key genetic reason for WS2 in this family,and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband.