Digenic or pseudo-digenic inheritance models in Noonan Syndrome and RASopathies

The project aims to investigate the role of digenic inheritance (DI) and pseudo-DI in Noonan Syndrome (NS) and propose two families as genetic models for functional studies to demonstrate DI and pseudo-DI hypotheses. The proposal comprises the following specific aims: a) to generate iPSCs from the two families’ members and their differentiation in cell types relevant for phenotype analysis; b) to study the additive effect of hypomorphic variants by CRISPR-Cas9 modification of iPSCs; c) to perform transcriptome and proteome studies in iPSC-derived cardiomyocytes; d) to generate mice with single or double mutations to study the modifier function of SOS1 variant; e) to generate zebrafish embryos with single or double mutated alleles for the analysis of developmental phenotypes related to the clinical manifestations of NS. Validation of DI and pseudo-DI in RASopathies would bring great benefits to pre-symptomatic diagnosis and clinical surveillance, allowing to define more effective guidelines for NS diagnosis and counselling.