Noonan syndrome and related disorders: The Gelb group established that Noonan syndrome (NS), an autosomal dominant disorder with a prevalence of ~1 in 2,000 livebirths, is caused by gain-of-function mutations altering signaling through the RAS/mitogen-activated protein kinase pathway. NS and several related disorders are now referred to as the RASopathies. We are currently engaged in two broad lines of inquiry for these traits:
- Elucidating disease pathogenesis: The Gelb research group is using human induced pluripotent stem cell (iPSC) technology to model various aspects of the RASopathies. We have already done so successfully for hypertrophic cardiomyopathy (HCM) and juvenile myelomonocytic leukemia. We have ongoing work on HCM and atrial arrhythmias.
- Discovery of therapeutics: Currently, there are no therapies for the RASopathies. Two disease characteristics, HCM and neurocognitive impairment, are particularly attractive targets for therapy. Working closely with the Cagan lab, we have screened drug and chemical libraries for efficacy using our Drosophila RAF1 model of NS. We have ongoing efforts to identify high efficacy/low adverse effect compounds using our fruit fly and iPSC RASopathy models.
Congenital heart defects: The Gelb group is one of five main sites for the NHLBI-funded Pediatric Cardiac Genomics Consortium (PCGC). The PCGC has recruited >10,000 individuals with CHD and, often, their unaffected parents. The consortium is performing leading genomics research including whole exome sequencing, whole genome sequencing, RNA-seq, and DNA methylation studies. The Gelb group performs a variety of analyses with these data. In addition, we are modeling CHD using human iPSCs derived from subjects with CHD and certain mutations.