Header menu link for other important links
X
Association of cardiomyopathy with MYBPC3 D389V and MYBPC3 Δ25bp intronic deletion in south asian descendants
Sangeetha Kandoi,
Published in American Medical Association
2018
PMID: 29641836
Volume: 3
   
Issue: 6
Pages: 481 - 488
Abstract
IMPORTANCE The genetic variant MYBPC3 Δ25bp occurs in 4%of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3 Δ25bp suggests that other stressors act in concert with MYBPC3 Δ25bp . OBJECTIVE To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3 Δ25bp . DESIGN, SETTING, ANDPARTICIPANTS South Asian individuals living in the United States were screened for MYBPC3 Δ25bp , and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. MAIN OUTCOMES AND MEASURES Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3 Δ25bp . RESULTS In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23%female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3 Δ25bp carrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3 Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3 Δ25bp carrier group. Strikingly, 9.6%of MYBPC3 Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3 Δ25bp , and D389V was only seen in the presence of MYBPC3 Δ25bp . In contrast to MYBPC3 Δ25bp , MYBPC3 Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients. CONCLUSIONS AND RELEVANCE MYBPC3 Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3 Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3 Δ25bp . © 2018 American Medical Association. All rights reserved.
About the journal
JournalJAMA Cardiology
PublisherAmerican Medical Association
ISSN23806583
Open AccessNo
Concepts (58)
  •  related image
    Biological marker
  •  related image
    Carrier protein
  •  related image
    MYOSIN-BINDING PROTEIN C
  •  related image
    Adult
  •  related image
    Aged
  •  related image
    Allele
  •  related image
    Article
  •  related image
    CARDIAC MUSCLE CELL
  •  related image
    Cohort analysis
  •  related image
    Controlled study
  •  related image
    Echocardiography
  •  related image
    Electrocardiogram
  •  related image
    Female
  •  related image
    Gene
  •  related image
    Gene expression
  •  related image
    GENE FREQUENCY
  •  related image
    Gene mutation
  •  related image
    Gene sequence
  •  related image
    Genetic screening
  •  related image
    Genetic variability
  •  related image
    GENOTYPE PHENOTYPE CORRELATION
  •  related image
    HEART EJECTION FRACTION
  •  related image
    HEART FUNCTION
  •  related image
    HEREDITY
  •  related image
    HETEROZYGOTE
  •  related image
    Human
  •  related image
    Human cell
  •  related image
    Human tissue
  •  related image
    HYPERTROPHIC CARDIOMYOPATHY
  •  related image
    INDUCED PLURIPOTENT STEM CELL
  •  related image
    Male
  •  related image
    MYBPC3 D389V GENE
  •  related image
    MYBPC3 GENE
  •  related image
    Next generation sequencing
  •  related image
    Prevalence
  •  related image
    Priority journal
  •  related image
    Prospective study
  •  related image
    SOUTH ASIAN
  •  related image
    United states
  •  related image
    VERY ELDERLY
  •  related image
    Adolescent
  •  related image
    ASIAN AMERICAN
  •  related image
    ETHNOLOGY
  •  related image
    Genetics
  •  related image
    Genotype
  •  related image
    HEART STROKE VOLUME
  •  related image
    HYPERTROPHIC CARDIOMYOPATHY
  •  related image
    Middle aged
  •  related image
    Mutation
  •  related image
    Pathophysiology
  •  related image
    Phenotype
  •  related image
    Young adult
  •  related image
    AGED, 80 AND OVER
  •  related image
    ASIAN AMERICANS
  •  related image
    CARDIOMYOPATHY, HYPERTROPHIC
  •  related image
    Carrier proteins
  •  related image
    Humans
  •  related image
    Stroke volume