Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.
OBJECTIVE
We sought to determine the frequency and phenotype of mutations in myosin binding protein C (MYBPC3) in a large outpatient cohort of patients with hypertrophic cardiomyopathy (HCM) seen at our tertiary referral center.


BACKGROUND
Mutations in MYBPC3 are one of the most frequent genetic causes of HCM and have been associated with variable onset of disease and prognosis. However, the frequency of mutations and associated clinical presentation have not been established in a large, unrelated cohort of patients.


METHODS
Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. Clinical data were extracted from patient records blinded to patient genotype.


RESULTS
Of 389 patients with HCM, 71 (18%) had mutations in MYBPC3. In all, 46 mutations were identified, 33 of which were novel (72%). Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-HCM, thin filament-HCM, or genotype-negative HCM with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of HCM or sudden death. Patients with multiple mutations (n = 10, 2.6%) had the most severe disease presentation.


CONCLUSIONS
This study defines the frequency and associated phenotype for MYBPC3 and/or multiple mutations in HCM in the largest cohort to date. In this cohort, unrelated patients with MYBPC3-HCM virtually mimicked the phenotype of those with mutations in the beta-myosin heavy chain. Patients with multiple mutations had the most severe phenotype.
Van Driest
Sara L
SL
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Vasile
Vlad C
VC
Ommen
Steve R
SR
Will
Melissa L
ML
Tajik
A Jamil
AJ
Gersh
Bernard J
BJ
Ackerman
Michael J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012518:Sarcomeres / Q000235:genetics; D013223:Statistics as Topic; D019210:Troponin I / Q000235:genetics; D020107:Troponin T / Q000235:genetics; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D019210:Troponin I; D020107:Troponin T; D000099163:Myosin Binding Protein C