探讨家系中携带COL1A2基因变异导致多个成员胎儿期及成年后成骨不全的临床特征。

选取中山大学孙逸仙纪念医院深汕中心医院产科1例COL1A2基因变异孕妇为研究对象，分析其胎儿及家庭成员的临床资料。中孕期获取羊水行染色体核型分析、染色体微阵列分析及家系全外显子组测序，有相关表型亲属进行基因变异位点Sanger测序验证，根据美国医学遗传学与基因组学学会指南(2015版)及ClinGen序列变异解读的更新进行致病性评级。

胎儿表现为双下肢长骨弯曲，其母亲、胞姐及舅舅婴儿时均表现为双下肢弯曲，随着年龄增长，表现为牙齿脆性大、易碎裂；家系全外显子组测序发现先证者携带COL1A2基因：NM_000089.4：c.1127G>T(p.Gly376Val)错义杂合变异，来源于母亲，遗传方式为常染色体显性遗传，致病性评级为可能致病性变异；胞姐、舅舅经Sanger测序验证均存在上述杂合变异；胎儿染色体核型分析：46, XN, inv (9) (p12q13)，CMA: arr(1－22)×2, (X, N)×1。

COL1A2基因c.1127G>T (p. Gly376Val)杂合变异是该胎儿的遗传学病因，COL1A2基因该位点变异临床表型具有时间特异性，在胎儿及婴儿时期表现为不伴有骨折的成骨不全，出生后随着年龄增长，该基因变异可致牙本质发育不全。

To investigate the clinical characteristics and outcome of fetal and adult period recurrent osteogenesis imperfecta caused by COL1A2 gene mutation in a family.

A pregnant woman with COL1A2 gene variant was selected as the research object in the department of obstetrics in Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University. Clinical data of her fetus and family members were analyzed. Invasive prenatal diagnosis was performed for chromosome G-banding karyotype analysis, chromosome microarray analysis (CMA) and family whole exome sequencing (Trio-WES). Relatives with related phenotypes were accepted Sanger sequencing. Pathogenicity was classified according to the American College of Medical Genetics and Genomics (ACMG) and the update to the interpretation of sequence variation in ClinGen.

The clinical symptom of the fetus was winding bones of the lower limbs. The gravida, the sibling sister and the uncle showed same symptom when they were infants. But the symptom turned to brittle teeth which must be repaired in adult. Trio-WES discovered the gene heterozygous variation in COL1A2 NM_000089.4: c.1127G>T(p.Gly376Val), which was inherited from mother. The inheritance patterns was autosomal dominant inheritance (AD). its pathogenicity was rated as likely pathogenic variation. The siblings and uncles carry the same variation by Sanger sequencing verification. Fetal chromosomal karyotype analysis: 46, XN inv (9) (p12q13). There was no abnormality in CMA.

The gene COL1A2 c. 1127G>T (p. Gly376Val) heterozygous mutation is the etiology of the fetus. The clinical phenotype of this locus variation in COL1A2 gene is time specificity. It was resulting in bone dysplasia without bone fracture in the fetal and neonatal period, and then the phenotype convert into dentinogenesis imperfecta as childhood.