A method of detecting a DSG2 autoantibody in a mammal is provided. The method includes contacting a biological sample obtained from a mammal with DSG2; and detecting the presence of DSG2 autoantibody bound to the DSG2 with a detectable anti-human antibody by detecting binding of the anti-human antibody to the DSG2 autoantibody. The method is useful to diagnose ARVC in a mammal.