Molecular Bases of Noonan Syndrome and Related Disorders

Noonan syndrome is the most common non-chromosomal disorder with congenital heart disease. While cardiovascular involvement (pulmonary valve stenosis and early-onset hypertrophic cardiomyopathy most commonly) is observed in 80% of individuals with this disorder, additional common features include reduced postnatal growth, skeletal and hematologic defects, facial dysmorphism, and variable cognitive deficits. Noonan syndrome is genetically heterogeneous. Seven disease genes (PTPN11, SOS1, NRAS, KRAS, RAF1, SHOC2 and BRAF), which encode for transducers participating in RAS signaling, had been identified by the applicant and collaborators before the beginning of the proposed research. Mutations in these genes were known to account for approximately 75% of affected individuals. The studies performed during this project have allowed the identification of two novel disease genes implicated in disorders clinically related to Noonan syndrome, and have provided novel molecular epidemiology and genotype-phenotype correlation data. They also have contributed significantly to our understanding of the molecular mechanisms underlying disease pathogenesis.