Molecular and Clinical Profile of patients referred as Noonan or Noonan-like Syndrome in Greece: a cohort of 86 patients

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Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, Rasopathies, due to the implication of mutations in genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease’s recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and Next-Generation-Sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype-phenotype analysis showed statistically significant differences regarding craniofacial dysmorphisms (p=0.005) and pulmonary valve stenosis (PS) (p<0.001) between patients harboring a mutation in any of the tested genes and mutation-free patients. Patients with at least one mutation had 6.71 times greater odds to develop PS compared to mutation-negative patients [OR=6.71, 95%; CI= (2.61, 17.27)]. PTPN11 positive patients showed higher frequency of epicanthal folds (p=0.004), ptosis (p=0.001) and coarseness (p=0.001) and lower frequency of neurological findings (p=0.006) , compared to patients with carrying mutations in other genes. Conclusion: Craniofacial dysmorphismand PS prevail among mutation positive compared to mutation negative NS and NS-like patients while neurological defects are less common in PTPN11 mutated NS patients compared to patients with mutations in other genes The significant prevalence of the Ras/MAPK mutations (17.4%), other than PTPN11, in Greek patients, highlights the necessity of a wider spectrum of molecular diagnosis.