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Editor—Hypertrophic cardiomyopathy (HCM) is an inherited disease (MIM 192600, 115195) of the heart muscle, characterised by unexplained left ventricular hypertrophy. HCM is also one of the major causes of sudden cardiac death,1sometimes occurring in young asymptomatic people.2-4Although sporadic forms do rarely occur,5 generally HCM has an autosomal dominant pattern of inheritance caused by mutations of the genes coding for proteins of the cardiac sarcomere. Subjects with HCM caused by mutations in the cardiac troponin T (cTNT) gene have been clinically shown to be at increased risk of sudden death,6 which may occur even in the absence of marked morphological abnormalities.7Since incomplete penetrance of the clinical phenotype, measured by ECG and echocardiographic parameters, is one of the hallmarks of “troponin” disease, the identification ofcTNT mutation in probands would facilitate identification of “at risk” relatives who may not fulfil clinical diagnostic criteria.
In the course of a study undertaken to characterise thecTNT mutation profile in HCM patients, we identified a cluster of mutations in exons 8 and 9. Five out of the 11 mutations published to date in this gene have been found in exons 88 and 9.7-10 We report here a novel Arg94Cys de novo mutation in a female patient presenting with HCM bringing the total of cTNT mutations to 12.
Four of the mutations found in exon 9, Arg92Trp, Arg92Gln, Arg94Cys, and Ala104Val, involve C→T transitions (or G→A transitions in the opposite strand) within CpG dinucleotides. Approximately 70% of the cytosines within CpG dinucleotides in the mammalian genome contain highly mutable 5-methyl-cytosine (5mC) residues. These residues are not randomly distributed and the majority of the genome is CpG depleted.11 Although some CpG dinucleotides are found within coding regions, most CpG residues are in CpG islands, …