Do HCN4 Variants Predispose to Thoracic Aortic Aneurysms and Dissections?

Hyperpolarization-activated cyclic nucleotide gated channel 4 plays a key role in the generation of sinus rate and rhythm. Mutations in the corresponding gene, , are associated with sinus bradycardia, left ventricular noncompaction cardiomyopathy (LVNC), and mitral valve disease (MIM#613123-Brugada Syndrome 8 and MIM#163800-Sick Sinus Syndrome 2). More recently, Vermeer and colleagues reported variants that co-segregated with ascending aortic dilatation, LVNC and/or sinus bradycardia in eight families, expanding the phenotype of rare variants to include thoracic aortic disease (TAD). Subsequently, Arbustini and colleagues questioned the association of thoracic aortic aneurysms with mutations because numerous rare variants were identified in in cases with TAD and other conditions, but none segregated with disease in families; and these rare variants were identified in cases with pathogenic and other rare variants in cardiovascular disease genes.