Dilated cardiomyopathy and sensorineural hearing loss - A heritable syndrome that maps to 6q23-24

Background-Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNH L) are prevalent disorders that occur alone or as components of complex mul tisystem syndromes. Multiple genetic loci have been identified that, when m utated, cause DCM or SNHL. However, the isolated coinheritance of these phe notypes has not been previously recognized. Methods and Results-Clinical evaluations of 2 kindreds demonstrated autosom al-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was eviden t by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the lar ger kindred (29 individuals) were used to perform a genome-wide linkage stu dy. polymorphic loci on chromosome 6q23 to 24 were coinherited with the dis ease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292. a l ocation that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidat e gene by nucleotide sequence analysis; no mutations were identified. Conclusions-A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at ri sk for serious heart disease, thereby enabling early intervention. Definiti on of the molecular cause of this syndrome may provide new information abou t important cell physiology common to both the ear and heart.