1658例颈项透明层增厚胎儿基因组拷贝数变异检测结果及出生结局

Copy number variation analysis and outcomes of 1658 fetuses with increased nuchal translucency

目的总结颈项透明层(nuchal translucency,NT)增厚胎儿的遗传学病因和预后,以指导产前咨询和诊断。方法回顾性纳入2014年8月至2021年12月于河南省人民医院因早孕期胎儿NT≥2.5 mm而接受介入性产前诊断[染色体核型分析和/或染色体微阵列分析或拷贝数变异(copy number variation,CNV)测序]的非高龄单胎妊娠孕妇(n=1658)。依据NT厚度(≥2.5~<3.0、≥3.0~<3.5、≥3.5~<4.5、≥4.5~<5.5、≥5.5~<6.5和≥6.5 mm组)和胎儿超声异常进行分组(孤立性NT增厚组、NT增厚合并软指标/非重大结构异常组和NT增厚合并重大结构异常组),比较不同组间介入性产前诊断结果及出生结局。采用χ^(2)检验和趋势χ^(2)检验进行统计学分析。结果以2.5 mm或3.0 mm为NT增厚切割值时,胎儿染色体数目异常检出率分别为15.8%(262/1658)和17.6%(252/1431)。染色体数目异常检出率随NT增厚而升高(χ^(2)趋势=180.75,P<0.001),由NT≥2.5~<3.5 mm组的6.6%(44/671)升至NT≥5.5 mm组的45.6%(113/248);致病/可能致病CNV(pathogenic/likely pathogenic CNV,P/LP CNV)的检出率随NT增厚无明显升高趋势(χ^(2)趋势=3.26,P=0.071),但以NT≥4.5~<5.5 mm组检出率最高(9.0%,19/211)。染色体数目异常+P/LP CNV的检出率在孤立性NT≥2.5~<3.0 mm与NT≥3.0~<3.5 mm组分别为5.3%(10/188)和9.6%(36/375),差异无统计学意义(χ^(2)=3.06,P=0.080),在孤立性NT≥3.5~<4.5 mm及NT≥2.5~<3.0 mm合并软指标/非重大结构异常组检出率分别高达12.7%(52/410)及24.1%(7/29),检出风险分别是孤立性NT≥2.5~<3.0 mm组的2.6倍(95%CI:1.3~5.2)和5.7倍(95%CI:2.0~16.4)。随NT增厚终止妊娠率逐渐升高(χ^(2)趋势=304.42,P<0.001),由NT≥2.5~<3.0 mm组的10.8%(23/212)升至NT≥6.5 mm组的90.7%(117/129)。排除染色体数目异常和P/LP CNV导致的妊娠终止,NT增厚胎儿活产率可达87.6%(862/984)。结论染色体数目异常检出率随NT增厚而升高。非高龄单胎妊娠孕妇胎儿NT≥2.5 mm伴或不伴软指标/结构异常均建议行介入性产前诊断。

Objective To analyze the genetic etiology and prognosis in fetuses with increased nuchal translucency(NT)in order to assist in the clinical prenatal genetic counseling and diagnosis.Methods This study retrospectively enrolled 1658 cases of singleton pregnancy(<35 years old)receiving invasive prenatal diagnosis,including karyotype analysis and/or chromosome microarray analysis or copy number variation(CNV)sequencing,due to NT value≥2.5 mm in the first trimester in Henan Provincial People's Hospital from August 2014 to December 2021.They were divided into different groups according to the thickness of NT(≥2.5-<3.0,≥3.0-<3.5,≥3.5-<4.5,≥4.5-<5.5,≥5.5-<6.5 and≥6.5 mm groups)and abnormal ultrasound findings(isolated increased NT group,increased NT complicated by soft markers/non-severe structural abnormality group and increased NT complicated by severe structural abnormality group).The results of invasive prenatal diagnosis and pregnancy outcomes were compared between different groups using Chi-square test and trend Chi-square test.Results The detection rates of numerical abnormalities of chromosomes were 15.8%(262/1658)and 17.6%(252/1431)when the NT thickness cut-off value were 2.5 mm or 3.0 mm,respectively.Overall,the detection rate of numerical abnormalities of chromosomes increased with thickness of NT(χ^(2)trend=180.75,P<0.001),ranging from 6.6%(44/671)in the NT≥2.5-<3.5 mm group to 45.6%(113/248)in the NT≥5.5 mm group.The incidence of pathogenic/likely pathogenic CNV(P/LP CNV)did not increased with NT thickness(χ^(2)trend=3.26,P=0.071),and the highest detection rate was observed in the NT≥4.5-<5.5 mm group(9.0%,19/211).The detection rate of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥2.5-<3.0 mm group and NT≥3.0-<3.5 mm group were 5.3%(10/188)and 9.6%(36/375),respectively,however,the difference was not statistically significant(χ^(2)=3.06,P=0.080).The detection rates of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥3.5-<4.5 mm group and NT≥2.5-<3.0 mm complicated by soft markers/non-severe structural abnormality group were 12.7%(52/410)and 24.1%(7/29),respectively,and the risk were 2.6 times(95%CI:1.3-5.2)and 5.7 times(95%CI:2.0-16.4)of the isolated NT≥2.5-<3.0 mm group,respectively.The pregnancy termination rate increased with the NT thickness(χ^(2)trend=304.42,P<0.001),ranging from 10.8%(23/212)in the NT≥2.5-<3.0 mm group to 90.7%(117/129)in the NT≥6.5 mm group.After exclusion of the pregnancies terminated due to numerical abnormalities of chromosomes and P/LP CNV,87.6%(862/984)of the fetus with increased NT were born alive.Conclusions The detection rate of numerical abnormalities of chromosomes increases with the thickness of NT.Invasive prenatal diagnosis is required for non-advance aged singleton pregnant women when fetuses present with isolated NT≥2.5 mm with or without soft markers/structural abnormalities.