COL11A1基因复合杂合变异所致纤维软骨增生Ⅰ型胎儿1例的产前表型及遗传学分析

Prenatal phenotype and genetic analysis of a fetus with Fibrochondrogenesis 1 due to compound heterozygous variants of COL11A1 gene

目的对1例超声检查提示肢体短小的胎儿进行产前遗传学诊断。方法以中国医科大学附属盛京医院妇产科2021年10月25日确诊的1例肢体畸形胎儿作为研究对象,采集胎儿羊水以及孕妇夫妇的外周血样,提取基因组DNA,通过全外显子组测序进行基因变异检测。对候选变异进行Sanger测序家系验证,并用在线软件对变异蛋白的结构进行预测。结果产前超声提示胎儿胸廓明显偏小,呈钟形,四肢明显偏短,面中部平坦,小鼻,鼻翼前倾,小下颌。引产儿CT检查显示肋骨宽短,干骺端呈杯状,长骨短,干骺端宽,呈哑铃状,胸椎弯曲。测序发现胎儿携带COL11A1基因c.2251G>T和c.3790G>T复合杂合变异,分别遗传自其父母。根据美国医学遗传学与基因组学学会(ACMG)相关指南均判定为疑似致病性。两个变异均可造成胶原蛋白重要结构(Gly-X-Y)的改变。结论上述研究确诊了1例罕见的由COL11A1基因复合杂合变异所致的纤维软骨增生Ⅰ型胎儿,对该家系的遗传咨询和再生育决策提供了重要的依据。

Objective To explore the genetic etiology of a fetus with short limbs identified by prenatal ultrasonography.Methods A fetus detected with short limb malformations at Shengjing Hospital Affiliated to China Medical University on October 25,2021 was selected as the study subject.Prenatal ultrasound and post-abortion imaging were carried out to determine the phenotypic characteristics of the fetus.Amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected.Following extraction of genomic DNA,whole-exome sequencing was carried out.Candidate variants were verified by Sanger sequencing.Online software was used to predict the structural changes of the mutant proteins.Results Prenatal ultrasound showed that the fetus had a small bell-shaped thorax,markedly shortened limbs,flat midface,a small nose with anteriorly tilted nostrils,and a small mandible.Post-abortion CT showed typical short and wide fetal ribs,cupped metaphyses at both ends,short long bones with wide metaphyses,resulting in a dumbbell-shaped appearance and curved thoracic vertebrae.Whole-exome sequencing revealed that the fetus had harbored compound heterozygous variants of the COL11A1 gene,namely c.2251G>T and c.3790G>T,both of which were predicted to alter the important Gly-X-Y structure of collagen protein.Sanger sequencing confirmed that the variants were respectively inherited from its parents.Conclusion A rare fetus with Fibrochondrogenesis type 1 due to compound heterozygous variants of the COL11A1 gene has been diagnosed.Above finding has enabled genetic counseling and reproductive guidance for this family.