We demcnstrate that mlssense mutations (Asplt5Asn; Glu18gGly) In the a-tropomyosln gene cause familial hypettrophk cardkmyopathy(FHC) Ilnked to chromosome 15q2. These flndlngs lmplkated components of the troponln complex as candidate genes at other FHC loci, pattkularly cardiac troponln T, which was mapped In this study to chromosome lq. Mlssense mutations (Ile7gAsn; Argg2Gln) and a mutatlon In the splice donor sequence of lntron 15 of the cardiac troponln T gens are also shown to cause FHC. Becaues atmyosln and cardiac troponln T as well as fi myosln heavy chain mutations cause the same phenotype, we conclude that FHC Is a disease of the sarcomere. Further, because the splice site mutation Is predicted to function as a null allele, we suggest that abnormal stolchlometry of sarcomerlc proteins can cause cardiac WpefiwW. lntroductlon