This study aims to investigate the value of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in fetuses with increased nuchal translucency (defined as NT above the 95th centile for the crown-rump length). A total of 374 singleton pregnancies with gestational ages ranging from 11 to 13 + 6 weeks were investigated. Ultrasound displayed increased NT and no detectable structural malformations in these fetuses. Pregnancies were divided into 4 groups according to the NT values: 95th centile-3.4 mm (114 cases); 3.5-4.4 mm (150 cases); 4.5-5.4 mm (55 cases); and ≥5.5 mm (55 cases). The possible chromosomal anomalies were all analyzed by CMA first. Furthermore, 24 cases with increased NT but negative CMA results were investigated by WES, and the outcomes were followed up. Among all the 374 cases, causative genetic defects were detected in 100/374 (26.7%) of the cases along with 9 variants of unknown significance (VOUS) by CMA. CMA testing yielded 30 pathogenic variants (30/55), accounting for a detection rate of 54.5%, and 1 VOUS in the group of NT ≥5.5 mm, indicating the highest detection rate in the 4 groups. The 24 cases of the CMA negative sub-cohort with WES analysis further yielded 2 VOUS and 3 likely pathogenic variants, including 2 dominant de novo mutations in SOS1 and ECE1 and 1 recessive inherited compound heterozygous mutation in PIGN, which are associated with cardiac defects. All 3 cases opted for termination of pregnancy (TOP). In addition, 2 cases with increased NT were negative by both CMA and WES analysis, and fetal demise occurred. In conclusion, for the investigation of fetuses with increased NT exome sequencing is suggested to be considered in cases with negative CMA findings. However, appropriate genetic counseling should be given to optimizing its utilization in prenatal diagnosis.

中文翻译：

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通过基因组技术对胎儿颈部半透明增加的胎儿进行基因检测

本研究旨在研究染色体微阵列分析 (CMA) 和全外显子组测序 (WES) 在颈部半透明性增加的胎儿中的价值（定义为 NT 高于 95 位的头臀长）。共调查了 374 名孕龄在 11 至 13 + 6 周之间的单胎妊娠。超声显示这些胎儿的 NT 增加且未检测到结构畸形。妊娠按 NT 值分为 4 组：第 95 百分位-3.4 mm（114 例）；3.5-4.4 毫米（150 箱）；4.5-5.4 毫米（55 箱）；≥5.5 mm（55例）。可能的染色体异常均先通过CMA进行分析。此外，WES 对 24 例 NT 增加但 CMA 结果阴性的病例进行了调查，并对结果进行了随访。在这374个案例中，CMA 在 100/374 (26.7%) 的病例中检测到致病基因缺陷以及 9 个意义不明的变异 (VOUS)。CMA检测有30个致病变异（30/55），检出率为54.5%，NT≥5.5mm组为1个VOUS，4组中检出率最高。带有 WES 分析的 CMA 阴性亚队列的 24 例病例进一步产生了 2 个 VOUS 和 3 个可能的致病变异，包括 SOS1 和 ECE1 中的 2 个显性从头突变和 PIGN 中的 1 个隐性遗传复合杂合突变，这与心脏缺陷相关。所有 3 例均选择终止妊娠 (TOP)。此外，2例NT增高的CMA和WES分析均为阴性，发生胎儿死亡。综上所述，建议在 CMA 结果为阴性的情况下考虑对 NT 外显子组测序增加的胎儿进行调查。然而，应给予适当的遗传咨询以优化其在产前诊断中的利用。