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Noonan syndrome (NS) is a common developmental disorder presenting with dysmorphic craniofacial features, heart defects, and short stature. It belongs to the group of RASopathies caused by germline mutations in genes encoding proteins involved in the RAS/MAPK signaling pathway. Although mutations in nine genes are known to cause NS, approximately 30% of the cases still have unexplained etiology. To identify the new causative genes, 42 patients with a clinical diagnosis of NS, who had negative results on Sanger sequencing of PTPN11, SOS1, and RAF1 (the most common NS genes), were selected for whole exome sequencing. In two patients, mutations in recently described new NS gene—RIT1 were found (c.244T>G [p.Phe82Val] and c.270G>C [p.Met90Ile]). Further analysis of a larger cohort (n = 64) of NS patients with classic Sanger sequencing revealed the presence of RIT1 mutation c.284G>C (p.Gly95Ala) in two additional patients. All the detected mutations were localized in switch II domain responsible for GTPase activity. The modeling of RIT1 protein structure revealed that the mutated amino acids and their interacting residues are evolutionary conserved and any residue replacement might change the structural stability and/or protein internal dynamics influencing catalytic activity of the protein. It seems that the identified mutations might alter protein function and therefore, the activity of ERK and P38 MAPK pathways, thus underlying the specific phenotype observed in NS patients. Our study independently confirms the role of RIT1 in the pathogenesis of Noonan syndrome. © 2014 Wiley Periodicals, Inc.

Background The aim of our study was retrospective analysis of 40 cases fetuses with down syndrome (T21) who had detailed sonography and echocardiography. Method Video tape analysis of 40 fetuses with T21 who had completed ultrasound and echocardiography examinations and completed neonatal follow-up in the same center. Results In our study the majority of cases 26 (65%) were low risk pregnancies. High risk pregnancies were in 14 (35%) cases. Congenital heart defect (72%) (AV-canal in 13/18 cases) was the most common anomaly diagnosed prenataly in fetuses with T21. Functional cardiac anomalies with normal heart anatomy were recorded also such as: dyspoportion and hypertrophy in 4/12 cases, tricuspid valve regurgitation, bright spot and pericardial effusion in 3/12 cases. Extracardiac malformations (25%) were diagnosed in fetuses with T21 such as: dudenal atresia, femur length shortening, pyelectasis bilateralis, face anomalies, sceletal malformations, hydrops fetalis. Conclusions 1. Congenital heart defect (72%) (AV-canal in 13/18 cases) was the most common anomaly diagnosed in fetuses with T21. 2. The most common extracardiac malformation was duodenal atresia 13/40 = 32.5% cases. 3. Fetal echocardiography can be usefull to identify in the group of low risk pregnancies, the potential patients for cytogenetic examinations of trisomy 21.