Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis
Creators: name: Di Girolamo, Raffaella
name: Rizzo, Giuseppe
name: Khalil, Asma
name: Alameddine, Sara
name: Lisi, Gabriele
name: Liberati, Marco
name: Novelli, Antonio
name: D’Antonio, Francesco
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Space Science
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Science Policy
subject: Infectious Diseases
subject: FOS: Health sciences

description: To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan. Medline and Embase databases were searched. Inclusion criteria were fetuses with NT &gt;95<sup>th</sup> percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and &gt; 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data. Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4–11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8–63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6–73.2) in those fetuses with NT &gt;5.5 mm and positive WES results. The 7.84% (95% CI 1.6–18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6–7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2–7.0) of cases. Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes.