A homozygous MITF mutation leads to familial Waardenburg syndrome type 4

作者：Xiuhong Pang, Xiao-Yong Zheng, Xuhui Kong, Yongchuan Chai, Yu Wang, Hua Qian, Bo Yang, Chao Wu, Jiusheng Chu, Tao Yang · 发表于：American Journal of Medical Genetics Part A · 年份：2018 · DOI：10.1002/ajmg.a.60693 · 被引用次数：29 · 研究领域：melanin and skin pigmentation、Biochemical Analysis and Sensing Techniques、RNA regulation and disease

Waardenburg syndrome (WS) is a genetic disorder characterized by hearing loss and pigmentary abnormalities with variable penetrance. Though heterozygous mutations in MITF are a major cause for Waardenburg syndrome type 2 (WS2), homozygous mutations in this gene and the associated phenotype have been rarely characterized. In this study, we identified a novel p.R223H mutation in MITF in a Chinese Han family with variable WS features. Both parents carried a heterozygous p.R223H mutation. They had normal hearing, and premature greying of the hair is their only pigmentary abnormality. In contrast, their two children both carried a homozygous p.R223H mutation and had classic WS features including profound hearing loss, heterochromia irides and marked pigmentary abnormalities in hair and skin. Interestingly, the two affected children also have persistent chronic constipation since the neonatal period, symptoms suggestive of Waardenburg syndrome type 4 (WS4). Our study revealed a likely association between homozygous mutations in MITF and WS4, which implies a dosage effect for the underlying pathogenesis mechanism.