Clinical and molecular analysis of RASopathies in a group of Turkish patients

Abstract

The 'RASopathies' are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty-one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype-phenotype correlations in RASopathies are relatively independent from the ethnic population background.

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

“…Intriguingly, some of these subjects were reported to have features suggestive of Costello syndrome, especially in early infancy. More recently, a number of reports confirmed the distinctive phenotype associated with the c.4A > G mutation, but also provided evidence for a wider clinical variability characterizing this disorder [Komatsuzaki et al, 2010;Digilio et al, 2011;Lee et al, 2011;Capalbo et al, 2012;Hoban et al, 2012;Gripp et al, 2013;Ş imşek-Kiper et al, 2013;Gargano et al, 2014;Zmolikova et al, 2014]. Table I summarizes the main clinical features of the SHOC2 cases reported in literature.…”

Clinical and Molecular Findings of Tunisian Patients with RASopathies

“…The following codons were previously described as major hotspots for recurrent mutations: asparagine 308 (25%) followed by tyrosine 63 (10%). [Lee et al, 2005;Tartaglia and Gelb, 2005;Takahashi et al, 2006] In other studied cohorts, however, asparagine 308 was not replicated as the most common mutation site [Bertola et al, 2006;Simşek-Kiper et al, 2013]. It is not clear whether these discrepancies reflect true differences that might be related to the population background.…”

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

“…RASopathies commonly predispose patients to short stature, developmental delay and cardiac abnormalities 29 . The syndrome (or syndromes) associated with each gene (or genes) is indicated by light grey arrows in the figure.…”

“…182). Many RASopathies predispose to tumours, including juvenile myelomonocytic leukaemia, rhabdomyosarcoma or neuroblastoma 29 . GRB2, growth factor receptor-bound protein 2; SHC, SRC homology 2 domain-containing.…”

“…Mutations in many other genes that encode components of the RAS–MAPK pathway also predispose patients to partially overlapping sets of manifestations (known as RASopathies), which can include tumours 29 (BOX 1). Patients with Noonan syndrome have a 4% risk of developing cancer by the age of 20 years, with JMML predominating and rhabdomyosarcoma, neuroblastoma and low-grade glioma occurring at lower incidences 30 .…”