Work in the Seidman laboratory (Dept of Genetics, HMS) is directed toward identifying gene defects that cause inherited heart disease and defining the pathways by which these mutations mediate disease. We begin by using human genetic techniques to identify disease-causing mutations that alter cardiac structure and function. The advent of whole exome sequencing approaches and whole genome sequencing approaches has lead to the discovery of a host of disease-causing mutations. Most recently we have focused on identifying gene mutations that cause congenital heart disease, dilated cardiomyopathy and hypertrophic cardiomyopathy.

Identified mutations are modeled in mice or iPS cells. The biochemical consequences of these mutations are elucidated in these model systems. For example, we have recently constructed iPS cells that carry truncation mutations in the TTN that encodes the large sarcomere protein titin using the CAS9/CRISPR gene editing approach. These iPS cells were grown in 3-D cultures and the consequences of these mutations on contraction were measured. Similarly approaches are being used to assess the consequences of chromatin modifying gene mutations that cause congenital heart disease and mutations that cause hypertrophic cardiomyopathy. These analyses have led to the recognition that TTN mutations cause disease by reducing the amount of functional protein, while hypertrophic cardiomyopathy mutations frequently cause disease by creating a 'poison polypeptide'. The mechanism(s) by which chromatin modifying gene mutations cause congenital heart disease remains largely unknown.