Table_1_Application of Copy Number Variation Detection to Fetal Diagnosis of Echogenic Intracardiac Focus During Pregnancy.DOCX

Echogenic intracardiac focus (EIF) is one of the most common ultrasound soft markers (USMs) in prenatal screening. However, the association of EIF with chromosomal abnormalities is still controversial. From January 2018 to April 2020, a total of 571 fetuses with USMs in our center were enrolled, among which 150 (26.27%) presented EIFs. We analyzed the karyotype anomalies and copy number variations (CNVs) in fetuses who presented EIFs by comparing their ultrasound indications, maternal ages and gestational stages. There were no statistically significant differences in the incidence of chromosomal abnormalities between fetuses with EIFs and the fetuses with USMs (4.00 vs. 7.71%, p = 0.112). Additionally, the incidence of chromosomal abnormalities was not related to maternal age (4.10% in maternal age below 35 yeas vs. 3.57% in maternal age above 35, p = 1.000). Interestingly, after 28 weeks of gestation, fetuses with EIFs showed more chromosomal abnormalities (20.00%) than that in the group before 28 weeks of gestation (2.22%, p = 0.014), and this result was attributed to the detection of pathogenic CNVs. After birth, 25 of children conducted cardiac development re-examination. Among them, 9 (36%, 9/25) were diagnosed with congenital heart disease, primarily patent foramen oval and ventricular septal defects (7/9, 77.77%). We concluded that the appearance of EIFs in early or mid-trimester would not indicate an increased risk of fetal chromosomal abnormalities. However, the persistence of EIFs in late trimester was associated with a higher risk of pathology-related CNVs and its persistent appearance may indicate heart development defects after birth. Thus, our results suggest that CNV detection has its advantages in prenatal diagnosis, especially for those with EIFs that persist in the third trimester.

心脏内强回声灶（Echogenic intracardiac focus, EIF）是产前筛查中最常见的超声软标志物（ultrasound soft markers, USMs）之一。然而，EIF与染色体异常的关联仍存在争议。本研究于2018年1月至2020年4月期间，纳入本中心确诊的571例超声软标志物阳性胎儿，其中150例（占比26.27%）表现为心脏内强回声灶。本研究通过对比胎儿超声表现、母亲年龄及妊娠孕周，分析了该类胎儿的染色体核型异常与拷贝数变异（copy number variations, CNVs）发生情况。结果显示，心脏内强回声灶阳性胎儿与其他超声软标志物阳性胎儿的染色体异常发生率无统计学显著性差异（4.00% vs 7.71%，p=0.112）。此外，染色体异常发生率与母亲年龄亦无显著关联：母亲年龄低于35岁组发生率为4.10%，≥35岁组为3.57%（p=1.000）。值得注意的是，妊娠28周及以后检出心脏内强回声灶的胎儿，其染色体异常发生率（20.00%）显著高于28周前检出组（2.22%，p=0.014），该差异主要源于致病性拷贝数变异的检出。产后共对25例患儿完成心脏发育复查，其中9例（占比36.00%，9/25）被诊断为先天性心脏病，以卵圆孔未闭及室间隔缺损为主（7/9，占比77.77%）。本研究结论认为，妊娠早中期检出的心脏内强回声灶并不提示胎儿染色体异常风险升高。然而，妊娠晚期持续存在的心脏内强回声灶与致病性拷贝数变异的高风险相关，且其持续存在可能提示产后心脏发育缺陷。综上，本研究结果提示拷贝数变异检测在产前诊断中具有独特优势，尤其适用于妊娠晚期持续存在心脏内强回声灶的胎儿。