解放军医学杂志2025，Vol.50Issue(2)：168-175,8.DOI:10.11855/j.issn.0577-7402.0966.2024.1017
EVC基因的复合杂合突变致Ellis-van Creveld综合征的家系遗传学分析:1例报告并文献复习
Genetic analysis of a family with Ellis-van Creveld syndrome caused by compound heterozygous mutations in the EVC gene:A case report and literature review
摘要
Abstract
Objective To report the genetic analysis of a family with a fetus suspected of Ellis-van Creveld(EVC)syndrome based on ultrasound findings such as ventricular septal defect(VSD),short long bones in the limbs and polydactyly,and to conduct a literature review to clarify the pathogenic cause.Methods A 27-year-old pregnant woman,who was pregnant for the first time and had no prior deliveries,was admitted to the prenatal diagnosis center of Shijiazhuang Obstetrics and Gynecology Hospital in October 2021.At 17 weeks of gestation,ultrasound detected multiple fetal malformations.The genomic DNA of the fetal proband's amniotic fluid cells and the parents'peripheral blood samples were sequentially subjected to chromosomal karyotype analysis,chromosomal microarray analysis(CMA),and whole exome sequencing(WES).Suspected pathogenic mutations were verified by Sanger sequencing in the proband and its parents.Subsequently,a Minigene in vitro experiment was used to analyze one splicing mutation.Meanwhile,databases such as PubMed were searched,and literature reports were combined for genetic analysis.Results Chromosomal karyotype analysis of the fetus showed no abnormalities,and CMA did not detect any copy number variation(CNV)with clinical significance.WES results revealed two mutations in the EVC gene(NM_153717.2)of the fetus:a nonsense mutation c.1405G>T(p.E469X)in exon 10 and a splicing mutation c.1886+5G>A in intron 13.Family verification using Sanger sequencing showed that the father was a carrier of the c.1405G>T(p.E469X)mutation in exon 10,and the mother was a carrier of the c.1886+5G>A mutation in intron 13.The compound heterozygous mutation of the fetus was inherited from the parents.According to the guidelines of the American College of Medical Genetics and Genomics(ACMG)for classifying genetic variations,c.1405G>T(p.E469X)was classified as likely pathogenic mutation(PVS1+PM2),and c.1886+5G>A was classified as likely pathogenic mutation(PM2+PM3_Strong).The Minigene experiment results showed that the c.1886+5G>A mutation caused a 115-bp segment retention in intron 13,further supporting its pathogenicity.Review of the literature showed that the typical clinical manifestations of EVC syndrome include short limbs,short ribs,postaxial polydactyly,nail and tooth dysplasia,and congenital heart defects.Gene mutations in EVC/EVC2 were found to be the main pathogenic cause through whole exome sequencing,with mutation types including missense mutations,large-scale duplications/deletions,in-frame microdeletions,nonsense mutations,frameshift mutations,and splicing mutations.Conclusions The compound heterozygous mutations in the EVC gene are the pathogenic cause of the fetus.The detection of these mutations expands the genetic variation spectrum of Ellis-van Creveld syndrome.关键词
骨骼发育不良/Ellis-van Creveld综合征/基因,EVC/全外显子组测序Key words
skeletal dysplasia/Ellis-van Creveld syndrome/gene,EVC/whole exome sequencing分类
临床医学引用本文复制引用
孙东兰,陈文琪,张晶,彭园园,袁玉凡,王朝希,郭清,张静..EVC基因的复合杂合突变致Ellis-van Creveld综合征的家系遗传学分析:1例报告并文献复习[J].解放军医学杂志,2025,50(2):168-175,8.基金项目
This work was supported by the Medical Science Research Project of Hebei Provincial Health Commission(20231661)and the Science and Technology Research and Development Plan of Shijiazhuang(221460465) 河北省卫生健康委医学科学研究课题(20231661) （20231661）
石家庄市科学技术研究与发展计划(221460465) （221460465）
