Characterization of Human POLR1A Phenotypes

We recently published our second paper describing an expanded cohort of individuals with heterozygous variants in POLR1A, as well as novel mouse models and in vitro assessments. We are continuing to collect clinical and genetic information from newly identified patients with heterozygous variants in POLR1A in an ongoing effort to better define POLR1A-associated phenotypes.

Collaborators

• Trainor Lab, Stowers Institute, Missouri
• Satoru Ide, National Institute of Genetics, Japan

Genetic and Developmental Mechanisms of Pulmonary Stenosis

We are analyzing genome sequencing from a large cohort of individuals with pulmonary stenosis (PS). Sequencing was accomplished via X01 HL 155057-01 and ongoing analysis funded by NHLBI R03HL159537-01A1. This PS case cohort was achieved through collaboration with Cincinnati Children's Discover Together Biobank and Heart Institute biorepository, Boston Children’s Hospital, and the Pediatric Cardiac Genomics Consortium.

Pulmonary stenosis is the most common congenital heart defect affecting individuals with RASopathies, a group of genetic syndromes caused by activating variants in genes of the RAS/MAP kinase pathway. Pulmonary stenosis can also occur due to pathogenic variants in genes outside of the RAS/MAP kinase pathway. We are studying valve development in mice and modeling it in vitro using patient-derived iPSC to better understand the mechanisms that drive abnormal valve development.

Collaborators

• Jing Chen, PhD
• Lisa Martin, PhD
• James Cnota, MD
• Amy Shikany, MS, CGC
• Alexander Opotowsky, MD, MMSc
• Katherine Yutzey, PhD
• Mingxia Gu, MD, PhD
• Amy Roberts, MD, Co-Director, Cardiovascular Genetics Center; Director, Cardiovascular Genetics Research Program, Boston Children's Hospital
• Bruce Gelb, MD, Pediatric Cardiac Genomics Consortium; Director, Center for Molecular Cardiology, Mount Sinai

Investigation into the Natural History and Metabolic and Molecular Basis of RASopathies

This is an IRB-approved study which oversees our ongoing efforts to provide answers to questions about the medical and developmental concerns facing individuals with RASopathies including Noonan syndrome, Costello syndrome, Cardiofaciocutaneous syndrome and Neurofibromatosis type I.