一例眼-面-心-牙综合征家系的遗传学分析及产前诊断并文献复习

Genetic analysis and prenatal diagnosis of a pedigree with oculo-facio-cardio-dental syndrome:a case report and literature review

目的分析眼-面-心-牙(oculo-facio-cardio-dental,OFCD)综合征家系的临床表型和遗传学病因。方法回顾分析在南京大学医学院附属鼓楼医院进行遗传咨询的1例孕17周孕妇的家系分析及产前诊断资料。采用全外显子组测序技术对孕妇及其配偶、上次妊娠引产胎儿行遗传学检测,采用染色体微阵列分析(chromosomal microarray analysis,CMA)、多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)及实时荧光定量聚合酶链反应(quantitative real time-polymerase chain reaction,Q-PCR)技术对检出变异进行验证。运用MLPA、PCR技术搭建的检测平台对孕妇此次妊娠的胎儿进行产前诊断,同时对家系其他成员进行了BCOR基因变异筛查。以"BCOR"为检索词,在ClinVar数据库中检索OFCD综合征相关病例,并进行变异类型和致病性分析。以"OFCD综合征""BCOR基因""oculo-facio-cardio-dental syndrome"为检索词,在中国知网及PubMed中检索,获取OFCD综合征相关病例,并对其临床表现进行分析。结果(1)孕妇(即先证者)存在先天性白内障、长脸、先天性房间隔缺损、严重的牙齿畸形,符合OFCD综合征的特征性表现。全外显子组测序结果提示,先证者及其引产胎儿疑似存在BCOR基因外显子DNA大片段单拷贝缺失。CMA检测、MLPA及Q-PCR技术证实缺失片段大小为105 kb,包含BCOR基因1~15号外显子。对先证者此次妊娠胎儿的羊水遗传学分析显示,胎儿为正常女性核型,未携带与先证者相同的BCOR基因拷贝数异常,出生后随访显示其生长发育正常,无OFCD综合征的特征性表现。先证者家系其他成员未见OFCD综合征的特征性表现,且均未检出BCOR基因拷贝数异常。(2)对ClinVar数据库中检索到的35例OFCD综合征的BCOR基因变异类型进行分析,发现BCOR基因的不同变异类型是导致Lenz小眼畸形综合征和OFCD综合征临床表现存在差异的原因。经文献检索获取的90例OFCD综合征病例中,国内仅有1例OFCD综合征的报道;OFCD综合征的特征性表现涉及眼部、面部、心脏、牙齿以及骨骼系统。根据先证者的临床表现结合BCOR基因的变异类型,明确了先证者及引产胎儿为OFCD综合征患者。结论OFCD综合征临床表现复杂,涉及BCOR基因多种变异类型。系统的遗传变异检测技术可应用于OFCD综合征的基因诊断和产前诊断。

Objective To analyze the clinical phenotypes and prenatal diagnosis of a pedigree with oculo-facio-cardio-dental(OFCD)syndrome.Methods A pregnant woman at 17 gestational weeks was admitted to the Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School in 2017 for genetic counseling.Genetic tests as performed for the proband(the pregnant woman),her husband,and the induced fetus of last pregnancy genetic test and the detected variants were analyzed and verified by chromosomal microarray analysis(CMA),multiplex ligation-dependent probe amplification(MLPA)and quantitative real time-polymerase chain reaction(Q-PCR).The detection platform established by MLPA and Q-PCR technology was used to perform prenatal diagnosis of the present pregnancy.Other family members were screened for BCOR gene mutation.Related mutation types were retrieved from ClinVar database with term of"BCOR",and related literature from CNKI and PubMed with terms of"OFCD syndrome","BCOR gene",and"oculo facio cardiac dental syndrome"to summarize the clinical manifestations,mutation type and pathogenesis of this disease.Results The proband has congenital cataracts,long face,congenital atrial septal defect,and severe dental malformations,which were consistent with the clinical features of OFCD syndrome.WES suggested that the proband and her induced fetus were suspected of having a large submicroscopic deletion of the exons of BCOR gene,which was confirmed by CMA,MLPA and Q-PCR,with a 105 kb deletion containing BCOR exons 1-15.The amniotic fluid genetic analysis of the present pregnancy showed that the fetus has a normal female karyotype,and did not carry the same BCOR gene copy number abnormality as the proband.The child grew and normally developed without any characteristic manifestations of OFCD syndrome during follow-up.Other families of the proband did not show clinical features of OFCD syndrone,and no BCOR gene copy number abnormality was detected.A total of 35 cases of BCOR gene mutation types related to OFCD syndrome were retrieved from ClinVar database.The data analysis revealed that the differences in clinical manifestations between Lenz microphthalmos syndrome and OFCD syndrome were mainly caused by different mutation types of BCOR gene.Among the 90 retrieved cases of OFCD syndrome obtained through literature,only one case was reported in China.Analysis of these 90 cases showed that the characteristic manifestations of OFCD syndrome,involving the eye,face,heart,teeth,and skeletal system.OFCD syndrome were confirmed in the proband and her induced fetus according to the clinical manifestation and the mutation type of BCOR gene.Conclusions The clinical manifestations of OFCD syndrome are complicated,caused by various mutation types of BCOR.Systematic molecular genetic technology can be effectively applied for gene and prenatal diagnosis of OFCD syndrome.