Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6).

F amilial hypertrophic cardiomyopathy (FHC) is typically characterised by left ventricular hypertrophy, diastolic dysfunction, and hypercontractility, and is often associated with disabling symptoms, arrhythmias, and sudden death. FHC shows both non-allelic and allelic genetic heterogeneity, and results from any one of more than 100 mutations in genes encoding sarcomeric proteins. Identified genes include those encoding b myosin heavy chain, the myosin regulatory and essential light chains, myosin binding protein C, troponin I, troponin C, a cardiac actin, and titin. 3 The FHC phenotype is characterised by hypertrophy, myocyte disarray and fibrosis, and results from the dominant negative expression of one of these (mainly missense) mutations. The resulting sarcomeric dysfunction leads ultimately, through mechanisms that remain obscure, to pathological left ventricular remodelling. However, as molecular defects are identified in only half the cases, it is likely that non-sarcomeric genes may also be responsible. Non-sarcomeric causes of FHC are largely uncharacterised, and may be associated with distinct or compound phenotypes. Similarly, hereditary sensorineural hearing loss shows a great degree of non-allelic and allelic genetic heterogeneity, and can be dominant, recessive, X linked, or mitochondrial. Hereditary sensorineural hearing loss is classified according to mode of inheritance and the presence of clinically detectable extra-auditory manifestations (syndromic deafness) or their absence (non-syndromic). 7 The distributions of mutant gene expression are not necessarily restricted to clinically affected organ systems, and mutant genes associated with ‘‘non-syndromic’’ deafness may therefore have subtle extra-auditory manifestations. Genetic syndromes restricted to a cardio-auditory phenotype include the long QT syndrome (LQTS) caused by mutations in KvLQT1 (KCNQ1) or in KCNE1, where QT prolongation has autosomal dominant expression (Romano Ward syndrome), but congenital sensorineural hearing loss with LQTS is autosomal recessive (Jervell and Lange-Nielsen syndrome). In the LQTS, cardiac structure is normal. Recently, Schonberger et al described a syndrome of dilated cardiomyopathy and sensorineural hearing loss which was linked to 6q23–24 in two families. dilated cardiomyopathy and sensorineural hearing loss penetrance were both age related, although sensorineural hearing loss onset was at a much younger age and appears to have been more penetrant. Here we describe a pedigree co-segregating progressive, late onset, autosomal dominant sensorineural hearing loss, QT interval prolongation, and cardiac hypertrophy. Linkage analysis indicates that the causative gene is located on chromosome 6q12. We have identified a mutation in MYO6, a gene encoding a non-muscle or unconventional myosin, in all affected members of the pedigree. METHODS Subjects Subjects were studied according to NHLBI (98-H-0100 and 99-H-0065) and NIDCD (97-DC-0180) protocols approved by the respective institutional review boards. Written consent