Ricerc@Sapienza

Background: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers
of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of
morbidity and mortality in patients with molecularly confirmed RASopathy.
Methods: A multicentric, observational, retrospective study was conducted in seven European cardiac centres
participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed
molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative
survival and restricted estimated mean survival.Multivariable regression analysis was used to assess the impact
of mutated genes on number of interventions and overall prognosis.
Results: Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention.
Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1,
5, 10, and 20 years, respectively. Restricted estimated mean survival at 20 years follow-up was 19.6 years.
Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic
cardiomyopathy (HCM) and age b2 years or young adults, as well as subjects with biventricular obstruction
and PTPN11 mutations had a higher risk of cardiac death.
Conclusions: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis
carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between
HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early
mortality, including immediate post-operative events and sudden death.