一例ASXL1基因变异致Bohring-Opitz综合征患儿的分析

Analysis of a child with Bohring-Opitz syndrome due to a variant of the ASXL1 gene

目的分析1例Bohring-Opitz综合征(BOS)患儿的临床特征及ASXL1基因突变情况,明确其遗传学病因。方法收集患儿的临床资料,采集患儿及父母的外周血,提取基因组DNA行家系全外显子组测序(WES),对候选可疑致病性变异进行生物信息学分析及Sanger测序验证。针对检出的致病变异,对该家系行羊水产前诊断。结果先证者,女,8岁,临床主要表现为全面性发育迟缓、重度智力障碍、小头畸形、额头鲜红斑痣、毛发浓密、肘和膝关节挛缩、宫内发育迟缓(IUGR)。家系WES提示先证者ASXL1基因c.4243C>T杂合突变(NM_015338.5),导致提前引入终止密码子(p.R1415*)。Sanger测序确证先证者存在c.4243C>T杂合变异,其父母均为c.4243C野生型。根据美国医学遗传学与基因组学学会(ACMG)指南并结合临床表现,推测ASXL1基因c.4243C>T变异为致病性变异(PVS1_Moderate+PS2_Moderate+PM2_Supporting),可导致BOS。随后进一步为先证者的再孕母亲进行羊水产前诊断,结果提示胎儿不携带该致病变异,随访至孩子出生后1周岁,一切正常。结论ASXL1基因c.4243C>T突变很可能是该家系BOS患儿的致病原因。基因检测结果可以为家系遗传咨询及产前诊断提供可靠依据。

Objective To analyze the clinical features and ASXL1 gene mutation in a child with Bohring-Opitz syndrome(BOS)and explore the genetic basis.Methods Clinical data of the child was collected,genomic DNA was extracted from peripheral blood samples of the child and her parents,and sequenced by whole exome sequencing(WES),and candidate pathogenic variant was confirmed by bioinformatics analysis and Sanger sequencing.Prenatal diagnosis with amniotic fluid cells was performed by detecting the pathogenic variant in the family.Results The proband,an 8-year-old girl,presented with generalized developmental delay,profound intellectual disability,microcephaly,flammeus nevus,thick hair,contractures at elbow and knees,and intrauterine growth restriction(IUGR).WES and Sanger sequencing revealed that the proband carry a c.4243 C>T heterozygous variant of the ASXL1 gene(NM_015338.5),which resulted in the premature introduction of stop code(p.R1415*),and the parents did not carry this variant.According to the American College of Medical Genetics and Genomics(ACMG)guidelines for interpretation of sequence variants,the variant was classified as pathogenic(PVS1_Moderate+PS2_Moderate+PM2_Supporting),which could lead to BOS.Subsequent prenatal diagnosis of amniotic fluid for the pregnant mother of the proband suggested that the fetus did not carry the pathogenic variant,and the follow-up was normal until the baby was 1 year old.Conclusion The variant c.4243 C>T of the ASXL1 gene might be the cause of BOS in the proband.The results of genetic testing can provide a reliable basis for genetic counseling and prenatal diagnosis.