The genetics of cardiac amyloidosis

Heritable cardiac amyloidosis (CA) is an underrecognized cause of morbidity and mortality in the USA. It results from the accumulation of the misfolded protein transthyretin within the myocardium, resulting in amyloid transthyretin-associated cardiomyopathy (ATTR-CM). Over 150 different pathologic point mutations within the transthyretin gene have been identified, each carrying variable clinical phenotypes and penetrance. In the USA, the most common cause of hereditary ATTR is the Val122Ile point mutation, with a prevalence of 3.4-4.0% in North Americans of African and Caribbean descent. Among Caucasians with hereditary ATTR-CM, the V30M mutation is the most commonly identified variant. Overall, the incidence of ATTR disease in the USA has been increasing, likely due to an increase in practitioner awareness, utilization of new non-invasive imaging technologies for ATTR diagnosis, and the growth of multidisciplinary amyloid programs across the country. Yet significant numbers of patients with evidence of left ventricular thickening on cardiac imaging, senile aortic stenosis, and/or symptoms of heart failure with preserved ejection fraction likely have undiagnosed CA, especially within the African American population. With the emergence of new disease-modifying therapies for ATTR, recognition and the prompt diagnosis of CA is important for patients and their potentially affected progeny. Herein, we review the genetics of heritable CA as well as the importance of genetic counseling and testing for patients and their families.