A Pain in the Neck: Lessons Learnt from Genetic Testing in Fetuses Detected with Nuchal Fluid Collections, Increased Nuchal Translucency versus Cystic Hygroma—Systematic Review of the Literature, Meta-Analysis and Case Series

Abstract

Fetal Nuchal fluid collections can manifest with two distinct presentations attributable to the same phenotypic spectrum: increased nuchal translucency (iNT) and cystic hygroma. The prenatal detection of these findings should prompt an accurate assessment through genetic counseling and testing, including karyotype, chromosomal microarray analysis (CMA) and multigene RASopathy panel. We performed a systematic review of the literature and meta-analysis, to calculate diagnostic yields of genetic testing in fetuses with iNT and cystic hygroma. We compared the results with a cohort of 96 fetuses with these isolated findings. Fetuses with isolated NT ≥ 2.5 mm showed karyotype anomalies in 22.76% of cases and CMA presented an incremental detection rate of 2.35%. Fetuses with isolated NT ≥ 3 mm presented aneuploidies in 14.36% of cases and CMA had an incremental detection rate of 3.89%. When the isolated NT measured at least 3.5 mm the diagnostic yield of karyotyping was 34.35%, the incremental CMA detection rate was 4.1%, the incremental diagnostic rate of the RASopathy panel was 1.44% and it was 2.44% for exome sequencing. Interestingly, CMA presents a considerable diagnostic yield in the group of fetuses with NT ≥ 3.5 mm. Similarly, exome sequencing appears to show promising results and could be considered after a negative CMA result.

Prenatal whole‐exome sequencing in fetuses with increased nuchal translucency

“…They established that the incremental CMA detection rate was 4.1% for isolated increased NT (≥3.5 mm). The percentage of pathogenic findings in this study was 5.5%, which is, therefore, in line with most other studies (Mastromoro et al, 2023).…”

“…In this series of 63 pregnancies with isolated firsttrimester increased NT (≥3.5 mm), WES identified pathogenic variants in three cases, yielding an incremental diagnostic rate of 4.8%. This discrepancy in diagnostic rate between this and previous studies may be attributable to different cohort sizes, cohort ascertainment, cut-off for increased NT, and criteria for variants interpretation (Mastromoro et al, 2023). In certain studies, such as one from Petrovski et al (2019), did not distinguish increased NT with or without structural abnormalities, leading to a high diagnostic rate in those with structural abnormalities.…”

“…Practice guidelines have recommended CMA as first‐tier test when a fetal anomaly has been detected by ultrasound or other fetal imaging and is rapidly becoming the preferred diagnostic test for fetuses with structural malformations (American College of Obstetricians and Gynecologists, Society for Maternal–Fetal Medicine, 2016; Committee on Genetics, Society for Maternal–Fetal Medicine, 2016). Most recently, Mastromoro et al (2023) performed a systematic review of the literature and meta‐analysis, to calculate diagnostic yields of genetic testing in fetuses with increased NT and cystic hygroma. They established that the incremental CMA detection rate was 4.1% for isolated increased NT (≥3.5 mm).…”

“…Among studies focused on isolated increased NT in the first trimester and used the 99th percentile (≥3.5 mm) as the cut‐off for increased NT, Yang et al obtained a 5.5% (4/73) increase in diagnostic rate over CMA using medical exome sequencing (Yang et al, 2020); Mellis et al obtained a diagnostic rate of 9.0% (14/155) using prenatal WES (Mellis et al, 2022). The recent systematic review and meta‐analysis by Mastromoro et al established an overall 2.44% diagnostic yield for exome sequencing in fetuses with isolated increased NT (≥3.5 mm) (Mastromoro et al, 2023). The great discrepancy in diagnostic rate questions the application of WES in fetuses with isolated increased NT.…”

“…Given that WES currently remains relatively costly and time‐consuming, and there is inevitably VUS and secondary findings which complicate data interpreting and results report, the RASopathy gene panel testing could be considered as an alternative detection method. Literature showed that, for cases with NT ≥3.5 mm and associated anomalies, the frequency of RASopathies, 7.69%, appears to be higher than in apparently isolated cases, being only 1.44% (Mastromoro et al, 2023). It was recommended that, after a normal CMA, RASopathy prenatal testing should be offered when any prenatal ultrasound finding suggestive of lymphatic dysplasia (cystic hygroma, increased NT or nuchal fold, hydrops, effusions, other lymphatic anomalies) or suggestive congenital heart disease (like valvular dysplasia and/or hypertrophic cardiomyopathy) is found alone or in association, except for isolated increased NT below 6 mm or isolated increased nuchal fold (Scott et al, 2021).…”