Since TTN is a known ACM associated gene, it is a likely candidate in the second family. TTN encodes for titin, the largest human protein with isoforms ranging from about 27.000 to 36.000 amino acids. Titin is functionally linked to the desmosome (and thereby to PKP2), since titin filaments are a key component of sarcomeres and connect to the transitional junction at the intercalated disk . In a cohort of 38 ACM families, Taylor et al. identified novel TTN mutations in 18% of the families . In addition to ACM, TTN has been associated with dilated, hypertrophic, and restrictive cardiomyopathy ; its association with hypertropic cardiomyopathy, however, is still under debate . The affected patient Fam2.II.1 and his father both harbor two rare heterozygous missense variants that are predicted deleterious. The Gln24857His variant is located in titin’s only kinase domain at a conserved position and is predicted to destabilize protein structure, while Arg23483His is located in one of the 132 Fn3 domains. Therefore, the Gln24857His variant is more likely to impair titin function than the Arg23483His variant, even though disease causal variants in repetitive titin domains have been reported . Studies with transfected cell lines have shown that heterozgyous mutations, in contrast to homozygous mutations, still allow for functional sarcomeres but may alter the organizational characteristics and impair the normal cardiac function . These findings agree well with the hypothesis that either one or both of these variants alter the structure of titin and only lead to ACM in combination with the PKP2 mutation.