20486例产前诊断样本中额外小标记染色体的核型结果分析

Karyotype analysis of small supernumerary marker chromosome in 20486 samples for prenatal diagnosis

目的探讨额外小标记染色体(small supernumerary marker chromosome, sSMC)在行产前诊断病例中的检出率、产前诊断指征及妊娠结局,为临床工作中sSMC的产前诊断和遗传咨询提供理论依据。方法回顾性分析2007年1月至2018年5月在北京大学第一医院妇产科产前诊断中心20 541例行产前诊断的病例资料,统计胎儿绒毛、羊水和脐带血标本经细胞培养和染色体G显带核型分析sSMC的检出率、产前诊断指征和妊娠结局。采用微阵列比较基因组杂交技术分析部分胎儿染色体异常来源。结果在培养成功的20 486例产前诊断样本中,共检出sSMC 20例,总检出率为0.98‰;其中,绒毛膜活检、羊膜腔穿刺和经腹脐静脉穿刺标本中,sSMC检出率分别为2.20‰(2/910)、0.74‰(14/18 824)和5.32‰(4/752);嵌合性核型12例。以夫妻一方染色体异常、胎儿超声结构异常、不良孕产史、孕妇高龄和唐氏综合征筛查高危为产前诊断指征的孕妇中,sSMC检出率分别为10.42‰(1/96)、2.65‰(4/1 507)、1.89‰(5/2 643)、0.83‰(8/9 624)和0.49‰(2/4 013)。11例孕妇进一步行微阵列比较基因组杂交分析,其中4例发现含有致病性基因拷贝数变异改变,分别由2q11.1-q12.1、2p12-p11.1和2q11.1-q12.1、7q11.21-q11.23、15q11.1-q13.3重复突变组成,后期均终止妊娠;7例检测为非致病性sSMC,其中1例引产,6例继续妊娠至足月分娩且妊娠结局良好,后期电话随访自述子代均未见异常。结论sSMC在行产前诊断病例中检出率较低,但夫妻一方染色体异常、胎儿超声结构异常和不良孕产史是发生sSMC最重要的指征。细胞遗传学与分子诊断技术相结合,可以对sSMC的性质、来源和致病性进行明确诊断,在产前遗传咨询和妊娠结局选择中具有非常重要的临床意义。

Objective To investigate the detection rate, clinical indications and pregnancy outcomes of pregnancies with prenatally diagnosed small supernumerary marker chromosome (sSMC) to provide a theoretical foundation for prenatal diagnosis and genetic counseling of sSMC. Methods This study retrospectively analyzed the clinical data of 20541 cases who underwent prenatal diagnosis at the Prenatal Diagnostic Center in the Department of Obstetrics and Gynecology in Peking University First Hospital from January 2007 to May 2018. The detection rate, diagnostic indications and pregnancy outcomes of the cases with sSMC were analyzed after cell culture and karyotyping. Array comparative genomic hybridization (aCGH) was used to analyze the origin of fetal abnormal chromosome in some cases. Results Prenatal diagnostic samples of 20 486 cases were successfully cultured, among which 20 (sSMC) were detected giving an detection rate of 0.98‰, while the figures in samples obtained through chorionic villus sampling, amniocentesis and umbilical cord blood sampling were 2.20‰(2/910), 0.74‰(14/18 824) and 5.32‰(4/752), respectively. Twelve cases of mosaic karyotype were also found. In gravidas for prenatal diagnosis indicated by maternal or paternal chromosomal abnormality, fetal structural anomalies on ultrasonography, adverse pregnant history, advanced maternal age and high risk of Down's syndrome, the detection rates of sSMC were 10.42‰(1/96), 2.65‰(4/1 507), 1.89‰(5/2 643), 0.83‰(8/9 624) and 0.49‰(2/4 013), respectively. Eleven cases were further analyzed with aCGH, four of which showed pathogenic copy number variants involving 2q11.1-q12.1, 2p12-p11.1 and 2q11.1-q12.1, 7q11.21-q11.23 and 15q11.1-q13.3 duplications and terminated the pregnancies. Seven cases carried non-pathogenic marker chromosomes, of which one terminated the pregnancy, while the other six continued to full-term with uneventful outcomes until follow-ups. Conclusions sSMC is hard to detect in prenatal diagnosis, but maternal or paternal chromosomal abnormalities, fetal structural anomalies on ultrasonography and adverse pregnancy and childbirth history are strong indications. Cytogenetics and molecular diagnosis combined can clarify the character, origin and pathogenicity of sSMC, and is of great clinical importance in prenatal genetic counseling and maternal decision making.