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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

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Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype

Konstantinos Kolokotronis1, Jirko Kühnisch2,3, Eva Klopocki1

  • 1Institute of Human Genetics, Biocenter, Julius-Maximilians-University, Würzburg, Germany.

Human Mutation
|March 30, 2019
PubMed

Insights

Biallelic inheritance of MYH7 or MYBPC3 gene variants can cause severe cardiomyopathy. Compound heterozygous states reveal insights into gene function and disease severity, impacting clinical presentation.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Dominant mutations in MYH7 and MYBPC3 are common causes of inherited cardiomyopathies.
  • These conditions often show variable symptoms and incomplete penetrance in families.
  • Biallelic inheritance, though rare, offers unique insights into gene function.

Purpose of the Study:

  • To investigate the genetic basis of severe cardiomyopathies in rare cases of biallelic inheritance.
  • To understand the impact of compound heterozygous variants in MYH7 and MYBPC3.
  • To correlate specific variant combinations with clinical phenotypes like left ventricular noncompaction.

Main Methods:

  • Case study analysis of three patients with compound heterozygous variants in MYH7 or MYBPC3.
  • Genetic sequencing to identify loss-of-function (LoF) and missense variants.
  • Assessment of protein levels in affected cardiac tissue.

Main Results:

  • Three cases presented with severe cardiomyopathy and left ventricular noncompaction due to compound heterozygous LoF and missense variants.
  • MYH7 haploinsufficiency showed a phenotype only in compound heterozygotes.
  • MYBPC3 haploinsufficiency combined with a de novo missense variant led to severe early-onset noncompaction, with reduced protein levels.

Conclusions:

  • Biallelic inheritance and complex variants (e.g., copy number variations, de novo mutations) should be considered in early-onset or atypical cardiomyopathies.
  • The clinical consequences of variants can differ significantly between heterozygous and compound heterozygous states.
  • Understanding these complex inheritance patterns is crucial for accurate diagnosis and genetic counseling.

Keywords:
MYBPC3MYH7biallelic mutationhaploinsufficiencyleft ventricular noncompaction cardiomyopathy

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