染色体微阵列分析对于明确中枢神经系统异常胎儿遗传学病因的价值

Value of chromosomal microarray analysis for the diagnosis of fetuses with anomalies of central nervous system

目的分析中枢神经系统(CNS)异常胎儿的染色体微阵列分析(CMA)结果并追踪其妊娠结局,探讨CMA在CNS异常胎儿中的病因学诊断价值。方法选取2014年6月~2020年12月因超声提示CNS异常至南京鼓楼医院产前诊断中心的636例胎儿为研究对象。根据超声表型,将CNS异常的胎儿分为脑室扩张组(n=441)、脉络丛囊肿组(n=41)、颅后窝池增大组(n=42)、全前脑组(n=15)、胼胝体发育不全(ACC)组(n=22)及其他异常组(n=75);此外,根据是否合并CNS以外的异常,将胎儿分为孤立性(n=504)及非孤立性(n=132)CNS组。收集胎儿的产前样本(羊水/穿刺绒毛/脐血)或流产组织,提取基因组DNA,进行CMA检测,并电话随访妊娠结局。结果共纳入636例CNS异常胎儿(包含89例流产组织),随访547例。CMA异常检出率为11.48%(73/636)。全前脑组、ACC组、脉络丛囊肿组、颅后窝池增大组、脑室扩张组、其他异常组的检出率分别为80%(12/15)、31.82%(7/22)、19.51%(8/41)、14.29%(6/42)、7.48%(33/441)、9.33%(7/75)。与孤立性CNS异常组相比,非孤立性CNS异常组的检出率显著偏高(6.35%vs.31.06%)(32/504vs.41/132)(χ2=62.867,P<0.001)。随访结果显示,CMA异常的52例胎儿中,1例发育正常,其余均已引产。CMA未见异常的434例胎儿中,377例活产(6例发育迟缓,其余均正常),57例引产;非孤立性CNS异常胎儿的不良妊娠结局率显著高于孤立性CNS异常胎儿(26.56%vs.10.54%)(17/64vs.39/370)(χ2=12.463,P<0.001)结论CNS异常的胎儿应通过CMA检测以明确遗传学病因。CMA未见异常的胎儿大多预后良好,但仍有出现神经系统异常表型的可能。合并其他结构异常的CNS异常胎儿的不良妊娠结局风险升高。

Objective To assess the value of chromosomal microarray analysis(CMA)for the diagnosis of fetuses with anomalies of the central nervous system(CNS)and summarize the outcome of the pregnancies and follow-up.MethodssA total of 636 fetuses from June 2014 to December 2020 who were referred the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects.Based on the ultrasound findings,the fetuses were divided into ventricular dilatation group(n=441),choroid plexus cyst group(n=41),enlarged posterior fossa group(n=42),holoprosencephaly group(n=15),corpus callosum hypoplasia group(n=22),and other anomaly group(n=75).Meanwhile,they were also divided into isolated(n=504)and non-isolated(n=132)groups based on the presence of additional abnormalities.Prenatal samples(amniotic fluid/chorionic villi/umbilical cord blood)or abortus tissue were collected for the extraction of genomic DNA and CMA assay.Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis.Results In total 636 fetuses with CNS anomalies(including 89 abortus tissues)were included,and 547 cases were followed up.The overall detection rate of CMA was 11.48%(73/636).The detection rates for the holoprosencephaly group,ACC group,choroid plexus cyst group,enlarged posterior fossa group,ventricular dilatation group and other anomaly group were 80%(12/15),31.82%(7/22),19.51%(8/41),14.29%(6/42),7.48%(33/441)and 9.33%(7/75),respectively.Compared with the isolated CNS anomaly group,the detection rate for the non-isolated CNS anomaly group was significantly higher(6.35%us.31.06%)(32/504 vs.41/132)(X2=62.867,P<0.001).Follow up showed that,for 52 fetuses with abnormal CMA results,51 couples have opted induced labor,whilst 1 was delivered at full term with normal growth and development.Of the 434 fetuses with normal CMA results,377 were delivered at full term(6 had developmental delay),and 57 couples had opted induced labor.The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses(26.56%us.10.54%)(17/64 vs.39/370)(X²=12.463,P<0.001).Conclusion Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause.Most fetuses with negative CMA result have a good prognosis,but there is still a possibility for a abnormal neurological phenotype.Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.