In recent studies on prenatal testing for Noonan syndrome (NS) in fetuses with an increased nuchal translucency (NT) and a normal karyotype, mutations have been reported in 9-16% of cases. In this study, DNA of 75 fetuses with a normal karyotype and abnormal ultrasound findings was tested in a diagnostic setting for mutations in (a subset of) the four most commonly mutated NS genes. A de novo mutation in either PTPN11, KRAS or RAF1 was detected in 13 fetuses (17.3%). Ultrasound findings were increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites. A second group, consisting of anonymized DNA of 60 other fetuses with sonographic abnormalities, was tested for mutations in 10 NS genes. In this group, five possible pathogenic mutations have been identified (in PTPN11 (n=2), RAF1, BRAF and MAP2K1 (each n=1)). We recommend prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the following additional features: polyhydramnios, hydrops fetalis, renal anomalies, distended JLS, hydrothorax, cardiac anomalies, cystic hygroma and ascites. If possible, mutation analysis of BRAF and MAP2K1 should be considered.

mutation analysis, Noonan syndrome, nuchal translucency, prenatal testing,
European Journal of Human Genetics
Department of Clinical Genetics

Croonen, E.A, Nillesen, W.M, Stuurman, K.E, Oudesluijs, G.G, van de Laar, I.M.B.H, Martens, L, … Yntema, H.G. (2013). Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. European Journal of Human Genetics, 21(9), 936–942. doi:10.1038/ejhg.2012.285