Diagnostic yield of next-generation sequencing in fetuses with isolated increased nuchal translucency: systematic review and meta-analysis

Ultrasound Obstet Gynecol. 2022 Jan;59(1):26-32. doi: 10.1002/uog.23746.


Objective: To determine the diagnostic yield of exome or genome sequencing (ES/GS) over chromosomal microarray analysis (CMA) in fetuses with increased nuchal translucency (NT) and no concomitant anomalies.

Methods: This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. PubMed, Scopus and Web of Science were searched for studies describing ES/GS in fetuses with isolated increased NT. Inclusion criteria were: (1) study written in English; (2) more than two fetuses with increased NT > 99th percentile and no concomitant anomalies; and (3) a negative CMA result considered as the reference standard. Only positive variants identified on ES/GS that were classified as likely pathogenic or pathogenic and determined to be causative of the fetal phenotype were considered. Risk was assessed as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance).

Results: Eleven studies reporting on the diagnostic yield of ES/GS in fetuses with isolated increased NT > 99th percentile were identified and included 309 cases. All studies were high quality according to Standards for Reporting of Diagnostic Accuracy. Overall, a pathogenic or likely pathogenic variant was identified on ES/GS in 15 fetuses, resulting in a pooled incremental yield of 4% (95% CI, 2-6%). Six (40%) of these fetuses had NT of 5 mm or more. The observed inheritance pattern was autosomal dominant in 12 cases, including four fetuses with Noonan syndrome, autosomal recessive in two cases and X-linked in one case.

Conclusions: There is a 4% incremental diagnostic yield of ES/GS over CMA in fetuses with increased NT > 99th percentile without a concomitant anomaly. It is unclear whether a NT cut-off higher than 3.5 mm may be more useful in case selection for ES/GS. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: diagnostic yield; exome sequencing; nuchal translucency; prenatal diagnosis.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Female
  • Fetus / diagnostic imaging*
  • Fetus / embryology
  • High-Throughput Nucleotide Sequencing / statistics & numerical data*
  • Humans
  • Microarray Analysis / statistics & numerical data*
  • Nuchal Translucency Measurement*
  • Predictive Value of Tests
  • Pregnancy
  • Prenatal Diagnosis / methods
  • Prenatal Diagnosis / statistics & numerical data*
  • Reference Values