Abstract

Rasopathies are a clinical group of disorders caused by dominant pathogenic variants in 29 genes within the RAS-MAPK pathway, which regulates cell growth, differentiation, aging, and the cell cycle. The most common Rasopathy is Noonan syndrome (NS), with PTPN11 variants detected in approximately 50% of cases, with 90% of these variants occurring in regions encoding the N-terminal SH2 and C-terminal catalytic domains. Prenatal findings include increased nuchal translucency (NT), lymphatic anomalies (such as cystic hygroma, pleural effusion, and ascites), cardiac anomalies, polyhydramnios, limb shortening, and macrocephaly. PTPN11 variants are found in 2-3% of fetuses with NT abnormalities (without chromosomal anomalies) and in >10% of cases with additional NS-related features. This study retrospectively analyzed PTPN11 gene results in 246 prenatal cases with NS-related ultrasound (USG) findings, excluding chromosomal anomalies. In 200 cases, target exons (3,4,7,8,13,14) were examined, while in 46 cases, the entire gene was analyzed using Sanger sequencing.
Five PTPN11 variants were detected in five cases (2%), including two novel variants (p.P107S and p.M504T). Two cases had isolated NT, while three had multiple USG findings. In six cases where no PTPN11 variant was found, SOS1 pathogenic variants were identified in two cases, and RAF1 pathogenic variants in one terminated pregnancy. The detection rate for NS-related pathogenic variants was 2.3% in both the isolated NT and multiple USG findings groups. Since 90% of pathogenic PTPN11 variants are located in targeted exons, prioritizing exon analysis as the initial step, followed by whole-gene and Rasopathy-related gene analysis when necessary.