Diagnostic Yield of Chromosomal Microarray Analysis in Fetuses With Isolated Increased Nuchal Translucency: A French Multicenter Study

Nuchal translucency (NT) is a collection of fluid at the back of the fetal neck; its thickness can be measured by ultrasound between 10 and 13 + 6 weeks of gestation. An increased thickness, often defined as an NT of greater than the 99th centile, which corresponds approximately to a threshold of 3.5 mm, is associated with a risk of chromosomal abnormalities, as well as genetic syndromes such as Noonan and Smith-Lemli-Opitz syndrome, and major structural birth defects. Increased NT is also associated with an increased risk of miscarriage and intrauterine fetal death. The prevalence of several congenital malformations, for example, heart defects, cleft lip and palate, and diaphragmatic hernia, is likewise higher than in the general population. Several studies have demonstrated the advantages of implementing chromosomal microarray analysis (CMA) in the prenatal setting, particularly when fetal anomalies, including enlarged NT, are detected. The researchers report on a retrospective, multicenter study, including 11 French hospitals and data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy testing, and the fetuses identified as euploid underwent CMA. Copy number variants (CNVs) detected were evaluated for clinical significance and classified into 5 groups: pathogenic CNVs, benign CNVs, CNVs predisposing to neurodevelopmental disorders, variants of uncertain significance, and CNVs not related to the phenotype (ie, incidental findings). In 121 fetuses (16.8%), an aneuploidy involving chromosome 13, 18, or 21 was detected by rapid aneuploidy testing, whereas the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were variants of uncertain significance. Additionally, there was 1 CNV (0.2%) that was unrelated to the reason for referral diagnosis (ie, an incidental finding), and the remaining 21 were benign CNVs, without clinical consequence. The researchers also identified 5 genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. The researchers concluded that performing CMA in fetuses with isolated increased NT will provide a significant benefit, because approximately 2% of cases have a cryptic pathogenic CNV. Furthermore, they detected genomic imbalances (ie, 1q21.1 and 15q11.2) that are associated with sporadic nonsyndromic congenital heart defect. The researchers recommend further investigation of the relationship between increased NT and these CNVs.