Christine Seidman

Christine Seidman, MD, director of BWH’s Cardiovascular Genetics Center, and colleagues have uncovered more than 50 mutations that occur in titin – a gene tied to cardiac failure and sudden death – and have gone on to predict and examine which of these mutations are benign and which ones are harmful. Their study appeared in Science Translational Medicine.

Titin (TTN) mutations are a known cause of the disease dilated cardiomyopathy (DCM), which can result in cardiac failure and sudden death, and affects about 1 in every 250 people. Although the frequency of the disease is known, the frequency of mutations in TTN has been unclear. The research team analyzed genetic and protein data from more than 5200 healthy and DCM subjects to uncover a range of mutations in TTN, some of which led to disease, but some of which did not. Mutations in the gene occurred in about two percent of the population. The researchers found that the benign or damaging effects of the mutations could be predicted based on where in the gene these mutations occurred and if they led to premature truncation of the encoded protein.

Many cardiomyopathy genes are among the American College of Medical Genetic and Genomics’ list of genes whose mutations should be reported back to patients. Understanding the frequency of mutations in TTN and other genes, as well as distinguishing damaging from benign mutations is critical as precision medicine gains traction and may allow clinicians in the future to stratify patients and tailor clinical treatment based on specific mutations and predictions about outcome.