To determine the mode of inheritance of hypertrophic cardiomyopathy (HC), 367 relatives from 70 families with HC were studied by M-mode and 2-dimensional echocardiography (2-D echo). Inspection of individual family pedigrees suggested that HC was genetically transmitted in 39 pedigrees (56%) and probably sporadic in 31 (44%). Of the 39 pedigrees with familial occurrence, 30 had patterns of inheritance that were most consistent with autosomal dominant transmission. A complex mathematical pedigree analysis determined that patterns of genetic transmission observed in the overall study group were not consistent with known models of autosomal dominant, autosomal recessive, or X-linked inheritance and did not support a unified concept of single-gene Mendelian transmission for all families. The proportion of first-degree relatives affected by HC was 22%, with HC most common in fathers of the proband and least common in offspring. About 20% of the affected relatives (10 of 53) appeared to have inherited a "subclinical" form of HC, in which the sole evidence of HC was the morphologic expression detectable only with echocardiography. Probands and affected relatives differed distinctly with regard to the expression of HC. Probands most often showed functional limitation (81%), subaortic obstruction at rest (53%), particularly diffuse distribution of left ventricular hypertrophy (59%) and marked septal thickening (mean 23 mm). In contrast, affected relatives were characterized by absence of functional limitation (72%) and subaortic obstruction (94%), localized and unusual sites of hypertrophy (60%) and only modest septal thickening (mean 17 mm).(ABSTRACT TRUNCATED AT 250 WORDS)