一例合并外耳发育不良的先天性糖基化障碍1y型患儿的SSR4基因变异分析

Analysis of SSR4 gene variant in a child with congenital glycosylation type 1y in conjunct with congenital dysplasia of external auditory canal

目的探讨1例合并外耳发育不良的先天性糖基化障碍1y型(congenital disorder of glycosylation type 1y,CDG-1y)患儿的遗传学病因。方法采用家系全外显子测序法(trio-whole exome sequencing,trio-WES)检测相关基因的变异,通过Sanger测序法对候选变异进行验证,并对其致病性进行生物信息学预测。结果患者为男性,10岁,主要表现为智力障碍、小头畸形合并先天性外耳发育不良。trio-WES检测发现患儿携带X染色体SSR4基因第4外显子c.302dupC(p.Y102Lfs*2)半合子移码变异,既往未见报道。Sanger测序在患儿父母中均未发现同样的变异,故属于新发变异(de novo)(PS2);在主要人群基因频率数据库中均未收录(PM2)。多种软件预测结果均提示其为致病变异(PP3)。UCSF chimera软件分析提示,该变异可使SSR4蛋白空间结构严重变形,导致生物学功能的丧失(PVS1+PM1)。根据ACMG指南,判断为致病性变异(PVS1+PS2+PM1+PM2+PP3)。结论SSR4基因c.302dupC(p.Y102Lfs*2)可能为患儿罹患CDG-1y的原因。上述发现拓宽了SSR4基因的变异谱以及CDG-1y的表型谱。

Objective To explore the genetic basis for a child with congenital disorder of glycosylation type 1y(CDG-1y)in conjunct with congenital dysplasia of external auditory canal.Methods Trio-whole exome sequencing(trio-WES)was carried out for the family.Candidate variant was verified by Sanger sequencing.Pathogenicity of the variant was predicted with a variety of bioinformatic tools.Results The proband,a 10-years-old boy,presented with mental retardation,microcephaly and dysplasia of external auditory canal.Trio-WES revealed that he has harbored a de novo frameshift variant c.302dupC(p.Y102Lfs*2)in exon 4 of SSR4 gene,which was unreported previously(PS2).The variant was absent in major allele frequency databases(PM2)and was predicted to be pathogenic by multiple bioinformatic tools(PP3).UCSF chimera software suggested that the c.302dupC(p.Y102Lfs*2)variant can induce significant alteration to the structure of SSR4 protein,resulting loss of function(PVS1+PM1).Based on the guidelines from the American College of Medical Genetics and Genomics,the variant was classified as pathogenic(PVS1+PS2+PM1+PM2+PP3)Conclusion The de novo frameshift variant c.302dupC(p.Y102Lfs*2)of the SSR4 gene probably underlay the child′s condition.Above finding has enriched the spectrum of SSR4 mutations and the phenotypic spectrum of CDG-1y.