Genetics

The Cardiovascular Genetics Program at Yale School of Medicine, directed by Arya Mani, MD, was established in 2010 to provide care for patients and families who are suspected of having inherited cardiovascular disease. The program has both clinical and research interests.

From a clinical perspective, the Cardiovascular Genetics Program works with individuals and their families who may be at risk for developing cardiovascular disease because of genetic factors. The genetic counselor, Arpita Neogi, CGC, MS, works alongside Dr. Mani to evaluate family history, establish the clinical diagnosis, offer genetic testing, provide risk assessment, and consider treatment options. The conditions seen in clinic include:

1. Inherited cardiomyopathies
2. Inherited heart rhythm disorders including Long QT syndrome, Brugada, CPVT, ARVD and sudden cardiac death
3. Inherited vascular conditions such as early onset familial forms of coronary artery disease, inherited syndromic and nonsyndromic disease of the aorta, such as Marfan syndrome and other connective tissue diseases.
4. Inherited lipid disorders
5. Inherited vascular disease
6. Congenital heart disease in adults

The program has established the first clinical center using whole exome sequencing for identification of established as well as novel disease genes.

The investigative arm of the program focuses on genetic evaluation of premature atherosclerosis, metabolic syndrome, and adult congenital disorders, particularly bicuspid aortic valve and patent ductus arteriosus. In addition, the center investigates novel genetic causes of all inherited cardiovascular disorders seen in the clinic.

Dr. Mani has also founded the Program for Cardiovascular Genetics at Yale, which is equipped with modern techniques of genotyping, including whole exome sequencing and computational biology. This program provides access for genetic testing and identification of both common and rare mutations for individuals with the most extreme inherited cardiovascular disorders. The Program for Cardiovascular Genetics is multidisciplinary in nature, working with general and interventional cardiologists, cardiomyopathy and heart failure group, electrophysiologists, echocardiographers, genetic counselors, nurses, primary care physicians, and research scientists to provide care.

Dr. Mani's laboratory is deeply engaged in system biology by combining functional genomics, epigenetics, transcriptomics, proteomics and gene editing in vivo and in vitro to understand the molecular mechanisms underlying metabolic syndrome, its traits, obesity, hyperlipidemia and hypertension and its complications in coronary artery disease (CAD), and type2 diabetes (T2D). The lab has recruited more than one thousand kindreds with early onset CAD and multiple metabolic risk factors for genetics and metabolic studies. Our work involves high throughput sequencing to identify disease genes, followed by characterization of the disease genes in vivo and in vitro. The group has mapped and identified a number of human disease genes for coronary artery disease and metabolic syndrome, patent ductus arteriosus (PDA) and bicuspid aortic valve and has published the findings in leading journals Science, Nature Genetics, NEJM, Cell Metab, PNAS, etc. These achievements have made his scientific group to one of the leading laboratories in investigation of metabolic syndrome.

Subsequent molecular and physiological studies in human subjects and animal models have allowed Dr. Mani to unravel many functions of genetic disorders and to identify novel targets for pharmaceutical intervention. Recent key discoveries of our laboratory are identification of novel gain of function mutations in DYRK1B (NEJM 2014) and loss of function mutations in the gene encoding serine protease CELA2A (Nat Genet 2019) which Mani’s lab has shown are associated with early-onset CAD, T2D and metabolic traits including fatty liver disease.