COL1A2新突变致胎儿严重成骨不全症1例报告并表型基因型关联性文献复习

A de novo COL1A2 gene mutation in a fetus with severe osteogenesis imperfect and phenotype-genotype correlation analysis

目的总结1例COL1A2新突变致胎儿严重成骨不全症（OI）的临床特征及基因突变的特点,为胎儿产前咨询提供依据。方法对产检B超检查示OI可能的胎儿流产组织抽提DNA进行基因型分析,自行设计COL1A1和COL1A2所有外显子及剪接区域的引物。利用Sanger测序法对胎儿行COL1A1和COL1A2基因外显子及剪接区域的测序分析并行父母验证。依据人类基因突变数据库（HGMD）专业版,对COL1A2突变所致疾病临床表型行文献复习。结果胎儿的COL1A1和COL1A2基因均检测出变异位点。COL1A2基因检测到杂合突变（c.3142G〉T,p.Glu1048Cys）在寡核苷酸多态性数据库、HGMD及Ⅰ型胶原蛋白突变数据库均未见报道,结合胎儿父母验证为新发突变,对比公共数据库及在线预测软件预测该突变类型为致病突变。在HGMD专业版中搜索COL1A2,共检索到387个COL1A2致病突变,与21种疾病及其亚型相关。92%的突变引起OI或其亚型,还可引起Ehlers-Danlos综合征或其亚型。结合COL1A2突变所致疾病临床表型行文献复习,本文报告胎儿符合Ⅱ型OI。结论产前通过超声影像结合基因分型诊断胎儿为COL1A2基因新发突变（c.3142G〉T,p.Glu1048Cys）所致Ⅱ型OI;COL1A2基因编码蛋白长链双螺旋的400~480氨基酸及MLBR 3区域中甘氨酸被天冬氨酸或谷氨酸替代,多导致严重表型的OI;本文为产前准确预测胎儿结局、指导临床决策提供依据。

Objective To summarize the clinical features and gene mutation characteristics of a de novo COL1A2 gene mutation in a fetus with severe osteogenesis imperfect（ OI）,and to provide evidence for prenatal counseling. Methods DNA was extracted from the fetal abortion tissues,and primers of the whole exons and splicing sites of COL1A1 and COL1A2 genes were designed. Using Sanger sequencing,the fetal sequences of the whole exons and splicing sites of COL1A1 and COL1A2 genes were analyzed and confirmed with the parents ＇ samples. According to HGMD,literatures on clinical symptoms of the diseases caused by COL1A2 mutation were reviewed. Results The variants on both COL1A1 and COL1A2 gene were detected. On COL1A2 gene a de novo heterozygous mutation（ c. 3142 G T,p. Glu1048Cys） was detected,which had never been reported in db SNP,HGMD and osteogenesis imperfecta Ehlers-Danlos syndrome variant databases. Compared with the common database and online prediction software the mutation was predicted to be a the disease-causing mutation. HGMD professional version was searched with ＂ COL1A2＂ and 387 disease-causing mutations were found to be related to 21 diseases or their subtypes. Ninety-two percent of the mutations caused OI or its subtypes; others caused Ehlers-Danlos syndrome or its subtype. Combined with the clinical symptoms of the disease caused by COL1A2 gene,the fetus was more consistent with the OI type Ⅱ. Conclusion A fetus OI type Ⅱ caused by a de novo mutation in COL1A2（ c. 3142 G T,p. Glu1048Cys） was diagnosed with prenatal ultrasound imaging and genotyping. Glycine in400 to 480 amino acid and MLBR 3 region of the protein encoded by COL1A2 gene replaced by aspartate acid or glutamic will cause sever OI. This article provides the basis for accurate prediction of fetal outcome and clinical decision-making.