Diagnostic yield of exome sequencing in fetuses with an isolated increased nuchal translucency: systematic review and meta-analysis.

Objective To determine the diagnostic yield of exome sequencing/genome sequencing (ES/GS) over chromosome microarray analysis (CMA) in fetuses with increased nuchal translucency (NT) and no concomitant anomalies. Method This systematic review was conducted in accordance with PRISMA criteria. All studies identified in PubMed, Ovid Medline and Web of Science describing ES/GS in fetuses with an isolated increased NT were included. Inclusion criteria were: a) English language studies with more than 2 NT cases; b) fetuses with increased NT > 99th percentile and c) no concomitant anomalies. Only positive variants classified as likely pathogenic or pathogenic determined to be causative of the fetal phenotype were considered. A negative CMA result was considered the reference standard. All studies were high quality according to STARD. Risk was taken as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance), heterogeneity was measured by the I2 method and Cochrane Q statistics. Results We identified 11 studies with data on ES/GS diagnostic yield including 309 individuals with isolated increased NT> 99th percentile. Overall, a pathogenic or likely pathogenic variant was found in 15 fetuses, resulting in a 4% (95%CI: 2% to 6%) incremental performance pool of ES. Six (40%) of these 15 fetuses showed an increased NT of 5mm or more. The observed inheritance pattern was autosomal dominant in 12 cases, including four Noonan syndromes, autosomal recessive in two cases, and X-linked in one fetus. Conclusion There is a 4% ES/GS diagnostic yield in fetuses with increased NT above the 99th percentile without concomitant anomalies. It is unclear whether a cut-off than higher 3.5mm would be more useful in case selection for ES/GS. This article is protected by copyright. All rights reserved.