Short Communication: The Cardiac Myosin Binding Protein C Arg502Trp Mutation

Abstract

MethodsStandard methods for DNA isolation and analyses were used and are described in the expanded Methods section, available in the Online Data Supplement at http://circres.ahajournals.org. ResultsThirty-four of 1414 (2.4%) consecutive unrelated HCM probands who underwent genetic testing (Supplement Methods), harbored the MYBPC3 Arg502Trp variant. MYBPC3 residue 502 has been highly conserved during evolution (Online Figure I). Insertion of tryptophan at position 502 substitutes a nonpolar hydrophobic residue for the polar uncharged residue arginine.MYBPC3 Arg502Trp cosegregated with HCM in families harboring only this sarcomere protein gene variant (Online Figure II). MYBPC3 Arg502Trp was absent in 545 healthy control subjects (nϭ95, this study; nϭ150 1 ; nϭ100 white Americans and nϭ100 African Americans 8 ; nϭ100 11 ). The combined calculated LOD score for HCM in MYBPC3 Arg502Trp familiesϭ4.04 (ϭ0, assuming penetranceϭ85% in subjects Ն20 years of age, and allele frequencyϭ0.001); the likelihood that MYBPC3 Arg502Trp and HCM cosegregated by random chance was less than 1/11 000. We conclude that MYBPC3 Arg502Trp is a pathogenic HCM mutation.Haplotype analyses were performed in 17 of the 34 MYBPC3 Arg502Trp families (Online Methods and Online Figure II) to determine whether a founding mutation in a common ancestor accounted for its high prevalence, or if MYBPC3 Arg502Trp arose repeatedly in unrelated HCM families. Haplotypes were assessed using short tandem repeat sequences that flank MYBPC3, 102 kb downstream and 188 kb upstream. Four unique haplotypes were identified (Table) with the most frequent haplotype, designated 4,5, seen in 13 families.Forty-three of 56 at-risk relatives in 34 families carried the MYBPC3 Arg502Trp mutation. Clinical information was available for 58 of 77 subjects (probands and family members) with the MYBPC3 Arg502Trp mutation (Online Table I). Fortyfive of 58 mutation carriers (78%) had clinical evidence of HCM, including hypertrophy, sudden cardiac death, or implanted cardioverter defibrillators (ICDs).The age of HCM diagnosis for Arg502Trp carriers relative to MYBPC3 truncation mutations and to MYH7 Arg719Trp, a mutation that causes severe HCM, carriers was compared (Figure, A). There was no significant difference in ages at diagnosis for 48 subjects who carried only the MYBPC3 Arg502Trp mutation versus carriers of MYBPC3 truncation mutations (Pϭ0.5). However, the age at diagnosis of HCM in carriers of MYH7 Arg719Trp was significantly earlier than for carriers of MYBPC3 Arg502Trp (PϽ0.0001). Whereas overt disease was recognized in nearly all carriers of MYH7 Arg719Trp by age 30, Ϸ50% of MYBPC3 Arg502Trp carriers lacked clinical evidence of HCM until after age 45 (Figure, A).Eight HCM subjects harbored both MYBPC3 Arg502Trp and another sarcomere protein gene mutation (Online Table III; Online Figure II, B). Based on patient age at the time of a significant adverse event (eg, age at sudden cardiac death, ICD implantation, myectomy, or cardiac transplantation), the clinical course of s...

Nationwide Study on Hypertrophic Cardiomyopathy in Iceland

“…In addition, Iceland's remote, rugged terrain and harsh environment may have produced negative effects on deleterious HCM mutations and may have contributed to the lower population prevalence of HCM in Iceland (1:1600) compared with the United States (1:500). 7 The founder mutation in the Icelandic population, similar to previously described founding mutations in Finland, 29 the Netherlands, 30 India, 31,32 Japan, 33 South Africa, 24 Spain, 34 France, 35 and the United States, 36 affects the MYBPC3 gene. Unlike deleterious HCM mutations, founder MYBPC3 mutations have a minimal effect on overall survival, particularly during the reproductive years of life.…”

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

“…Although initial studies supported the notion of mutation-specific clinical outcomes, 25 subsequent studies 26 and the identification of the vast clinical and genetic heterogeneity in HCM have limited the clinical utility of genotype in guiding management. 1,27 In the current study, MYH7 mutation carriers were found to be significantly younger, and they presented at a younger age, as compared with MYBPC3 mutation carriers. Mutations in specific genes did not correlate significantly with clinical features, but the number of gene mutations correlated with some measures of disease severity, specifically the occurrence of an OHCA or SCD in the proband.…”

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

“…In these adult cases, a more severe HCM phenotype is generally seen, characterized by an earlier age of onset around the second decade or during childhood (Table 2). 6,14,15,[20][21][22][23][24][25][26][27][28][29][30] In a recent study on sarcomeric protein gene variants in childhood-onset HCM, 6 out of 84 children (7%) had compound variants. 6 This suggests that a gene-dosage effect might be responsible for manifestations at a younger age.…”