两个Coffin-Siris综合征家系的ARID1B基因变异分析

Analysis of ARID1B gene variants in two Chinese pedigrees with Coffin-Siris syndrome

目的通过对两个Coffin-Siris综合征家系先证者的临床表征及基因变异分析,揭示其可能的遗传发病机制,为家系的遗传咨询提供依据。方法应用全外显子组测序技术对两例先证者进行致病原因筛查,结合临床表型确定可能致病的候选基因,用Sanger测序法对先证者及其家系成员进行变异验证。结果WES检测结果显示家系1先证者ARID1B基因存在c.5467delG(p.Gly1823fs)杂合变异。家系2先证者检出ARID1B基因c.5584delA(p.Lys1862fs)杂合变异。Sanger测序结果表明两家系先证者父母ARID1B基因均为野生型,经检索人类变异数据库,两变异均为未报道过的新变异。根据美国医学遗传学与基因组学学会指南,ARID1B基因的c.5467delG和c.5584delA变异均为致病变异(PVS1+PS2+PM2)。结论ARID1B基因c.5467delG(p.Gly1823fs)及c.5584delA(p.Lys1862fs)可能分别为两家系的致病原因,基因检测结果为家系的遗传咨询提供了依据。

Objective To explore the genetic basis for two Chinese pedigrees affected with Coffin-Siris syndrome(CSS).Methods Whole exome sequencing(WES)was carried out for the probands.Candidate variants were verified by Sanger sequencing of the probands and their family members.Results The two probands were respectively found to harbor a heterozygous c.5467delG(p.Gly1823fs)variant and a heterozygous c.5584delA(p.Lys1862fs)variant of the ARID1B gene,which were both of de novo in origin and unreported previously.Based on the guidelines of American College of Medical Genetics and Genomics,both variants were predicted to be pathogenic(PVS1+PS2+PM2).Conclusion The c.5467delG(p.Gly1823fs)and c.5545delA(p.Lys1849fs)variants of the ARID1B genes probably underlay the CSS in the two probands.Above results have enabled genetic counselling and prenatal diagnosis for the pedigrees.