Molecular bases of Noonan Syndrome and related disorders

Congenital heart disease (CHD) is the most common birth defect and a major cause of birth defect-related deaths. Similarly, hypertrophic cardiomyopathy (HCM) in childhood represents a major and difficult challenge in terms of patient management and survival. RASopathies constitute the most common family of non-chromosomal disorders associated with CHD and HCM, with an estimated aggregate prevalence of 1:1,500 live births. This family of disorders includes Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and an increasing number of other clinically related diseases sharing dysregulation of RAS signaling as common pathogenetic mechanism. Besides the cardiac involvement, major features of these disorders include defective postnatal growth, developmental delay, skeletal defects, and variable predisposition to certain pediatric cancers. Most of these conditions are genetically heterogeneous. Understanding the molecular causes of RASopathies is a requisite to diagnose and treat these disorders effectively as well as for a more effective patient management and risk assessment. While the completed research has provided insights into the molecular basis of disease, there are fundamental questions about disease pathogenesis that remain unanswered. Moreover, a large fraction of RASopathies still remains unexplained molecularly. Major goals of this research project are to identify novel disease genes implicated in these developmental disorders, understand the molecular mechanisms implicated in disease pathogenesis, and assess more precisely the prevalence, diversity and clinical relevance of mutations affecting newly and previously identified RASopathy genes to delineate the phenotypic diversity resulting from mutations affecting these genes and their associations with specific developmental defects.