利用全外显子测序技术确诊1例常染色体显性遗传性耳聋大家系为穆-韦综合征

Whole exome sequencing helps diagnose Muckle-Wells syndrome in a Chinese family with autosomal dominant hearing loss

目的·分析探讨1例被误诊为非综合征型耳聋的中国人群穆-韦综合征大家系的遗传学特征。方法·对1例耳聋来访者进行病史、家族史、全身和听力学检査,绘制家系遗传图谱并进行遗传学特征分析。通过定向捕获联合二代测序技术,对先证者进行已知138个耳聋相关基因的外显子及其侧翼内含子序列的筛査,对3名患病和1名不患病的家系成员进行全外显子测序分析,并用Sanger测序方法对候选基因突变进行基因型-表型共分离验证。结果·该耳聋家系共3代,现存家系成员11人。问诊得知11人中有耳聋患者9人,均表现为双侧迟发性、渐进性听力下降,符合常染色体显性遗传规律。使用定向捕获联合二代测序技术,排除138个已知耳聋基因,最终由全外显子测序识别了一个NLRP3基因的E313K突变,Sanger测序确认该位点突变与此家系耳聋表型共分离。结论·首次在中国人群中确诊1例常染色体显性遗传性耳聋大家系为穆-韦综合征,并发现NLRP3基因的E313K突变为其致病基因突变。

Objective · To analyze the genetic characteristics of Muckle-Wells syndrome in a Chinese family based on a case misdiagnosed as nonsyndromic deafness. Methods · The medical history, family history, physical, and audiological examinations were performed for a deaf patient. The familial pedigree was drawn and genetic characteristics were analyzed. Screening for exons and flanking intron sequences in 138 genes known to be associated with deafness was performed for the proband with deafness-targeted next generation sequencing. The whole exon sequencing was conducted for 3 affected and 1 unaffected familial members. The genotype-phenotype co-segregation was verified with Sanger sequencing for Candidate mutations. Results · The deafness family contained 11 members with 3 generations. Inquiries revealed that 9 of them were deaf with bilateral, late onset, and progressive hearing loss, which was consistent with autosomal dominant inheritance. One hundred and thirty-eight genes known to be associated with deafness were ruled out with deafness-targeted next generation sequencing. The whole exon sequencing revealed an E313K mutation in NLRP3 and the co-segregation between E313K and the deafness phenotype in this family was confirmed by Sanger sequencing. Conclusion · A Chinese family with an autosomal dominant hereditary hearing loss was diagnosed as Muckle-Wells syndrome for the first time. E313K mutation in the NLRP3 gene was identified as the causative gene mutation.