一个Cockayne综合征家系的临床特征及致病基因突变分析

Analysis of clinical characteristics and pathogenic gene mutations in a family of Cockayne syndrome

目的:分析一个Cockayne综合征家系临床特征和致病基因突变。方法:分析该家系成员临床特征及影像学资料,采集先证者及其家系成员外周血,并提取基因组DNA,对先证者进行2742个基因靶向捕获扩增,进行高通量测序分析,并通过Sanger测序对患者及家属的致病突变位点进行验证。结果:该家系先证者表现出生长发育迟缓、智力低下、特殊面容以及脑萎缩、钙化等表现;其弟弟临床表现类似。高通量测序及Sanger测序发现先证者为ERCC8基因复合杂合突变,包括c.394-398 delTTACA(p.L132fs*6)的缺失移码突变和c.37G>T(p.E13*)的无义突变,分别来源于表型正常的父亲和表型正常的母亲;其妹妹为ERCC8 c.394-398 delTTACA突变携带者,表型正常。产前诊断结果提示胎儿ERCC8基因c.394-398、c.37均为野生型,新生儿随访表型正常。结论:先证者的发病基础为母源性和父源性的ERCC8基因突变,该研究可为Cockayne综合征的遗传学咨询及产前诊断提供依据。

Aim:To analyze the clinical characteristics and pathogenic gene mutations of a family of Cockayne syndrome.Methods:The clinical characteristics and imaging data of the family members were analyzed,the peripheral blood of the proband and his family members were collected and genomic DNAs were extracted,and the proband was subjected to targeted capture and amplification of 2742 genes with high-throughput sequencing analysis,Sanger sequencing was used to verify the presence of pathogenic mutations in the proband and the relatives.Results:The proband of this family showed growth retardation,mental retardation,special face,and brain atrophy and calcification.His brother had the similar clinical manifestation.High-throughput sequencing and Sanger sequencing revealed the proband had complex heterozygous mutations in the ERCC8 gene,including deletion frameshift mutations in c.394-398 delTTACA(p.L132fs*6)and nonsense mutation c.37G>T(p.E13*).The nonsense mutations were respectively derived from his parents with normal phenotypes;his sister was a carrier of the ERCC8 c.394-398 delTTACA mutation and had normal phenotypes.The prenatal diagnosis showed that the fetal ERCC8 genes c.394-398 and c.37 were both wild type,and the neonatal follow-up showed normal phenotype.Conclusion:The pathogenesis of Cockayne syndrome in the proband is based on the maternal and paternal ERCC8 gene mutations.Our findings provide a basis for genetic counseling and prenatal diagnosis of family members.