Yield of RASopathy gene panel in fetuses with isolated and non-isolated increased nuchal translucency

Noonan syndrome (NS) is a multisystem disorder belonging to a group of genetic disorders called RASopathies. Genetic workup for increased nuchal translucency (NT) includes a RASopathy gene panel, especially if chromosomal microarray (CMA) is normal. Despite smaller cohort studies associating increased NT with NS, the diagnostic yield of a RASopathy gene panel in this population is not well defined. Our objective was to determine the diagnostic yield of a RASopathy gene panel in fetuses with isolated and non-isolated increased NT with normal CMA or karyotype. A systematic review and meta-analysis was conducted in accordance with PRISMA criteria. We searched 4 electronic databases between January 1977 and July 2022 for studies describing the yield of targeted RASopathy gene panels in fetuses with increased NT, usually defined as ≥ 3.5 mm, with normal CMA or karyotype. Pathogenic and likely pathogenic variants were considered diagnostic. Subgroup analysis was performed of yield in isolated and non-isolated cases. Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2) checklist was used. 14 studies (1942 cases, 139 diagnoses) were included. Overall diagnostic yield was 7.1%. Of 11/14 studies that reported detailed ultrasound findings, the diagnostic yield was 7.0% (22/315) in isolated increased NT cases and was 5.3% (55/1046) in non-isolated cases (p-value: 0.265). Yield was higher in cohorts that underwent CMA testing (9.0%) than those that had karyotype alone (5.8%) (p-value 0.007). Cardiac anomalies were the most common additional finding in non-isolated cases. Median number of genes tested per panel was 6 (range: 1-20). The diagnostic yield of a RASopathy gene panel in increased NT cases ranges from 5.3 – 7.0%. While prior literature suggests a lower yield in isolated cases, our meta-analysis found the overall yield to be similar between the two cohorts. As many studies conducted testing for 1-4 genes, it is reasonable to presume a higher yield overall with current NGS panels of 14 genes or more.View Large Image Figure ViewerDownload Hi-res image Download (PPT)