一例Krabbe病患者家系的产前诊断和基因突变分析

Prenatal diagnosis and analysis of genetic mutation in a family with Krabbe disease

目的探讨一例Krabbe病患者的遗传病因,并对家系成员进行基因突变分析及产前诊断。方法应用全外显子测序技术对Krabbe病患者进行致病突变筛查,结合临床表型,确定候选基因的致病位点,Sanger测序验证夫妻双方GALC基因,孕妇进行绒毛穿刺和羊水穿刺,对GALC基因测序并进行产前诊断。结果全外显子测序结果显示家系中Krabbe病患者存在GALC基因c.599C>A(p.Ser200*)和c.461C>A(p.Pro154His)位点复合杂合变异,其父亲为c.461C>A(p.Pro154His)位点杂合变异携带者,母亲为c.599C>A(p.Ser200*)杂合变异携带者。绒毛和羊水检测GALC基因为c.461C>A(p.Pro154His)位点杂合变异。结论 GALC基因c.599C>A(p.Ser200*)和c.461C>A(p.Pro154His)位点复合杂合变异是该家系中Krabbe病患者的发病原因,胎儿绒毛和羊水检测结果与先证者不同,为该家系遗传咨询和产前诊断提供有力证据,有效预防出生缺陷。

Objective:To investigate the genetic etiology of a case with Krabbe disease,to analyze the genetic mutation and prenatal diagnosis in a family.Methods:Whole exome sequencing(WES)was used to screen pathogenic mutations in Krabbe patients,and pathogenic candidate genes were determined based on clinical phenotypes.The GALC gene in spouses were validated by Sanger sequencing.GALC gene was sequenced and prenatal diagnosis was performed by villus puncture and amniocentesis.Results:Whole exome sequencing has identified two heterozygous variants of GALC gene in a patient with Krabbedisease,namely c.599C>A(p.Ser200*)and c.461C>A(p.Pro154His).Sanger sequecing confirmed that c.461C>A(p.Pro154His)was derived from her father,while c.599C>A(p.Ser200*)was derived from her mother.Villi and amniotic fluid were identified GALC gene c.461C>A(p.pro154his)heterozygous variation.Conclusion:The compound heterozygous variation of c.599C>A(p.Ser200*)and c.461C>A(p.Pro154His)of the GALC gene may underlie Krabbe disease in the affected family.The sequencing results of villi and amniotic fluid are different from those of the proband,providing evidence for genetic counseling andprenatal diagnosis of the affected family and effectively preventing birth defects.