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目的:分析Waardenburg综合征(WS)2型家系的临床表型特征,并探讨其分子病因,为WS家系提供遗传咨询。方法:收集7个WS2型家系和散发病例(14例患者)的临床资料,分析其临床表型特征,均签署知情同意书并获取血样,提取基因组DNA,聚合酶链反应扩增MITF、SNAI2、SOX10和EDNRB基因编码区全部外显子,在ABI自动测序仪上进行正反向测序,并进行测序结果和相关数据信息的分析。结果:WS2型患者的临床表型特征最常见的是听力障碍(10/14,71.4%)、雀斑(7/14,50.0%)、虹膜异色(6/14,42.9%)和早白发(5/14,35.7%);耳聋表型比较一致,均表现为先天性双耳极重度感音神经性聋,雀斑表型不同于国外WS患者的皮肤低色素改变。突变检测发现WS02家系MITF基因第3号外显子c.328C>T杂合突变(p.R110X),其他家系和散发病例均未检测到这4个基因的致病性突变。结论:WS2型患者表型特征多样,棕褐色雀斑沉着可能是国内WS患者皮肤色素异常表现的一种特殊形式。MITF基因突变R110X是导致WS02家系发病的分子病因,其他家系突变检测阴性提示存在其他未知的WS2致病基因或者拷贝数变异的可能。
OBJECTIVE: To analyze the clinical phenotypic characteristics of the Waardenburg syndrome (WS) type 2 pedigree and explore its molecular etiology to provide genetic counseling for WS pedigrees. Methods: The clinical data of 7 WS2 pedigrees and sporadic cases (14 patients) were collected. The clinical phenotypes were analyzed. All informed consent forms were signed and blood samples were collected for genomic DNA extraction. MITF, SNAI2, SOX10 and EDNRB gene coding region of all exons, ABI automated sequencer forward and reverse sequencing and sequencing results and related data analysis. Results: The most common phenotypic characteristics of WS2 patients were hearing loss (10/14, 71.4%), freckle (7/14, 50.0%), iris heterochromatic (6/14, 42.9% (5 / 14.35.7%). The deafness phenotypes were more consistent, all showed congenital bipolar severe sensorineural deafness. The freckle phenotype was different from the skin hypochromic changes of WS patients in other countries. Mutations detected c.328C> T heterozygous mutation (p.R110X) of exon 3 of MITF gene in WS02 pedigree. No pathogenic mutation of these 4 genes was detected in other pedigrees and sporadic cases. CONCLUSIONS: The phenotypic characteristics of WS2 patients are diverse. The tanned freckles may be a special form of skin pigmentation abnormalities in patients with WS. MITF gene mutation R110X is the molecular cause of WS02 pedigree pathogenesis. The negative detection of other familial mutation suggests the possibility of other unknown WS2 causative genes or copy number variation.