Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome

Waardenburg syndrome (WS) is a rare disorder characterized by distinctive facial features, pigment disturbances, and sensorineural deafness. There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups, but the data from Chinese patients with WS remains poor. Herein we report 18 patients from 15 Chinese WS families, in which five cases were diagnosed as WS1 and the remaining as WS2. Clinical evaluation revealed intense phenotypic variability in Chinese WS patients. Heterochromia iridis and sensorineural hearing loss were the most frequent features (100% and 88.9%, respectively) of the two subtypes. Many brown freckles on normal skin could be a special subtype of cutaneous pigment disturbances in Chinese WS patients. PAX3, MITF, SNAI2, and SOX10 genes mutations were screened for in all the patients. A total of nine mutations in 11 families were identified and seven of them were novel. The SOX10 mutations in WS2 were first discovered in the Chinese population, with an estimated frequency similar to that of MITF mutations, implying SOX10 is an important pathogenic gene in Chinese WS2 cases and should be considered for first-step analysis in WS2, as well as MITF.     

Waardenburg综合征Ⅱ型患者MITF基因突变分析

Waardenburg综合征(WS)是临床上常见的常染色体显性遗传性耳聋综合征, MITF基因突变与部分Waardenburg 综合征Ⅱ型(WS2)病例的发病有关。MITF属于碱性螺旋-环-螺旋亮氨酸拉链转录因子家族, 能调节酪氨酸酶基因, 参与黑色素细胞的分化。文章报道了1个携带MITF基因点突变的3代Waardenburg综合征Ⅱ型中国家系。先证者表现为先天性重度感音神经性聋、虹膜异色、面部雀斑; 其他家系成员除一名仅表现为先天性耳聋外, 均表现为颜面、上肢雀斑和/或早白发。患者可检测到c.639delA杂合突变, 该突变在MITF基因第7外显子上产生了终止密码子(p.I220X), 突变产生的截短的MITF蛋白没有DNA结合活性。该突变是WS2病例中第3个位于MITF第7外显子的突变, 尚未见报道。该突变与已报道的位于第7外显子其他两个突变仅相差1个碱基, 氨基酸改变十分相似, 但在表型上有显著差别, 提示遗传背景对WS临床表型有重要影响。     

The value of MLPA in Waardenburg syndrome

Waardenburg syndrome (WS) is an autosomal-dominant neurocristopathy characterized by sensorineural hearing loss, pigmentary abnormalities of the iris, hair, and skin, and is responsible for about 3% of congenital hearing loss. Point mutations in PAX3 have been identified in more than 90% of affected individuals with WS Type 1/WS Type 3. MITF point mutations have been identified in 10-15% of individuals affected with WS Type 2 (lacking dystopia canthorum). Multiplex ligation-dependent probe amplification (MLPA) is now a standard technology in the molecular genetics laboratory to detect copy number changes in targeted genes. We employed MLPA for PAX3 and MITF in a cohort of patients submitted with a diagnosis of WS1, 2 or 3 who were sequence negative for PAX3 and/or MITF. All coding exons of PAX3 and exons 1, 2, 3, and 10 of MITF were included in the MLPA assay. MLPA on 48 patients with WS 1 or 3 revealed 3 PAX3 whole gene deletions (2 WS1; 1 WS3), 2 PAX3 partial gene deletions [WS1, exon 1 and promoter (1st report); WS1, exons 5-9], and 1 partial MITF deletion ("WS1", exons 3-10) (6/48 approximately 12.5%). MLPA on 41 patients with WS2 and 20 patients submitted with a diagnosis of either WS1 or WS2 revealed no copy number changes. The detection of both partial and whole gene deletions of PAX3/MITF in this clinical cohort increases the mutation detection yield by at least 6% and supports integrating MLPA into clinical molecular testing primarily for patients with WS1 and 3.