SOX10基因变异所致Waardenburg综合征4C型耳聋一个家系的基因检测及产前诊断

Genetic testing and prenatal diagnosis for a Chinese pedigree affected with Waardenburg syndrome type 4C due to heterozygous deletion of SOX10 gene

目的探究1个Waardenburg综合征4C型(WS4C)耳聋家系的遗传学病因,并为该家系的胎儿进行产前诊断。方法选取2020年10月23日因双耳感音神经性聋就诊于郑州大学第一附属医院的1例女性耳聋先证者及其家系成员(2代3人)作为研究对象,收集先证者及其家系成员的临床资料。应用全外显子组测序对先证者进行基因检测,使用多重连接探针扩增(MLPA)方法对测序结果进行验证并对先证者父母和胎儿进行检测。结果先证者为1岁8个月女性,双耳极重度感音神经性聋,长期慢性便秘,双眼虹膜异色。先证者母亲为双耳极重度耳聋患者,双眼虹膜异色。先证者父亲听力正常,虹膜颜色正常。基因测序结果提示先证者存在SOX10基因第1~4外显子杂合缺失变异,先证者母亲及其胎儿检测到SOX10基因杂合缺失,父亲SOX10基因拷贝数正常。依据美国医学遗传学与基因组学学会遗传变异分类标准与指南,变异评级为致病性变异(PVS1+PM2_Supporting+PP1+PP4)。胎儿检测到该变异,将来发展为WS4C型耳聋患者的可能性大,先证者父母在遗传咨询后选择了引产。结论SOX10基因第1~4外显子杂合缺失变异考虑是该WS4C家系致病原因,可用于指导产前诊断。

Objective To explore the genetic basis for a Chinese pedigree featuring congenital profound syndromic deafness and chronic constipation,and provide prenatal diagnosis for a high-risk fetus.Methods Whole-exome sequencing was carried out to analyze the sequences of genes associated with hereditary deafness,and multiplex ligation-dependent probe amplification(MLPA)was used to verify the candidate variant in the proband′s parents and the fetus.Results The proband was found to have harbored a heterozygous deletion of SOX10,a pathogenic gene associated with Waardenburg syndrome type 4C(WS4C).The same deletion was found in her mother(with profound syndromic deafness and chronic constipation)and the fetus,but not in her father with normal hearing.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG)and Association for Molecular Pathology(AMP),the SOX10 gene deletion was predicted to be a pathogenic variant(PVS1+PM2_Supporting+PP1+PP4).Conclusion The pedigree was diagnosed with WS4C,which has conformed to an autosomal dominant inheritance.Deletion of the entire SOX10 gene,as a loss-of-function variant,probably underlay its pathogenesis.Above finding has facilitated genetic counseling and prenatal diagnosis for this family.