Yield of RASopathy Gene Panel in Karyotype-Normal or Microarray-Normal Fetuses With Increased Nuchal Translucency: A
Jennifer E Powel1, Julie P Barbera1, Megan B Raymond1
1Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Hackensack Meridian Jersey Shore University Medical Center, Neptune, New Jersey; the Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, and the Department of Obstetrics and Gynecology and the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania; the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, Rhode Island; and the Department of Obstetrics & Gynecology, Maimonides Medical Center, Brooklyn, New York.
Objective:
To characterize the diagnostic yield of RASopathy gene panels performed due to increased nuchal translucency (NT) measurements with normal karyotype or chromosomal microarray (CMA) results or both.
Data Sources:
PubMed, OVID, SCOPUS, CINAHL, and ClinicalTrials.gov databases were searched from inception through January 8, 2025 (PROSPERO CRD 42023353582).
Methods Of Study Selection:
Studies were deemed eligible for inclusion if the cohort consisted of fetuses with increased NT with normal karyotype or CMA or both that were tested with a targeted RASopathy gene panel. Quality assessment and critical appraisal of included studies were independently conducted using the Quality Assessment tool for Diagnostic Accuracy Studies. The primary outcome was the diagnostic yield of a RASopathy gene panel in fetuses with increased NT and normal karyotype or CMA or both. Nuchal translucency measurement, associated congenital abnormalities, the presence of cystic hygroma, and the number of genes evaluated in each study were collected.
Tabulation Integration And Results:
Our systematic review identified 1,800 cases that met inclusion criteria across 14 studies. The RASopathy gene panel identified a diagnostic variant in 114 cases, for an overall yield of 8.1% (0.081, 95% CI, 0.036-0.139). In fetuses with isolated increased NT, the RASopathy gene panel identified a diagnostic variant in 3.3% of cases (0.033, 95% CI, 0.006-0.074). In fetuses with additional ultrasound abnormalities, the RASopathy gene panel identified a diagnostic variant in 15.1% of cases (0.151, 95% CI, 0.011-0.381). Cardiac abnormalities were the most common associated finding. When a cystic hygroma was identified, total diagnostic yield was 18.4% (0.184, 95% CI, 0.110-0.270).
Conclusion:
Testing for RASopathies with a targeted gene panel identified a diagnostic variant in 3.3% with isolated increased NT and 15.1% with nonisolated increased NT after normal karyotype or CMA or both.
Systematic Review Registration:
PROSPERO, CRD42023353582.
