Abstract
BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.
Highlights
MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, its prevalence varies between populations
Ever since the first mutation in the beta myosin heavy chain (MYH7) gene was described as a cause of hypertrophic cardiomyopathy (HCM) in 1990 [3], mutations have been identified in 11 genes that codify cardiac sarcomeric proteins [4,5,6,7]
On the other hand we provide useful information for the clinicians, like in mutation K600fs (Figure 2), our data confirms the pathogenicity of a previously described mutation in just one case without available clinical data or familial study [18]. (iii) Severe and early forms of Hypertrophic Cardiomyopathy (HCM) and sudden cardiac death (SD) in patients with mutations in MyBPC3 It has been suggested that mutations in gene MyBPC3 are associated with a light clinical and morphological expression and with a late development of hypertrophy [11,35]
Summary
MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder, characterized by unexplained left ventricular hypertrophy, myocyte hypertrophy and disarray, and interstitial fibrosis [1,2]. It has a frequency of 0.2% in the adult population and is a major cause of sudden cardiac death (SD) in young people (< 35 years old).
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