Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark 
of a rare familial or sporadic unclassified heart disease of heterogeneous 
origin. NVM results presumably from a congenital developmental error and has 
been traced back to single point mutations in various genes. The objective of 
this study was to determine the underlying genetic defect in a large German 
family suffering from NVM. Twenty four family members were clinically assessed 
using advanced imaging techniques. For molecular characterization, a genome-wide 
linkage analysis was undertaken and the disease locus was mapped to chromosome 
14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 
(encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced, 
leading to the identification of a previously unknown de novo missense mutation, 
c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid 
in the myosin subfragment-1 (R281T). In silico simulations suggest that the 
mutation R281T prevents the formation of a salt bridge between residues R281 and 
D325, thereby destabilizing the myosin head. The mutation was exclusively 
present in morphologically affected family members. A few members of the family 
displayed NVM in combination with other heart defects, such as dislocation of 
the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A 
high degree of clinical variability was observed, ranging from the absence of 
symptoms in childhood to cardiac death in the third decade of life. The data 
presented in this report provide first evidence that a mutation in a sarcomeric 
protein can cause noncompaction of the ventricular myocardium.