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Hum Mutat. 2019 Mar 29. doi: 10.1002/humu.23757. [Epub ahead of print]

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

Author information

1
Institute of Human Genetics, Biocenter, Julius-Maximilians-University, Würzburg, Germany.
2
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center (ECRC), a Joint Cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
3
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
4
Department of Medical Genetics, Alberta Health Services, Calgary, Alberta, Canada.
5
Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
6
DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
7
Comprehensive Heart Failure Center (CHFC) and Department of Medicine I, University and University Hospital Würzburg, Würzburg, Germany.
8
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Cardiology, Charité - University Medicine Berlin, Berlin, Germany.

Abstract

Dominant mutations in the MYH7 and MYBPC3 genes are common causes of inherited cardiomyopathies, which often demonstrate variable phenotypic expression and incomplete penetrance across family members. Biallelic inheritance is rare but allows gaining insights into the genetic mode of action of single variants. Here, we present three cases carrying a loss-of-function (LoF) variant in a compound heterozygous state with a missense variant in either MYH7 or MYBPC3 leading to severe cardiomyopathy with left ventricular noncompaction. Most likely, MYH7 haploinsufficiency due to one LoF allele results in a clinical phenotype only in compound heterozygous form with a missense variant. In contrast, haploinsufficiency in MYBPC3 results in a severe early-onset ventricular noncompaction phenotype requiring heart transplantation when combined with a de novo missense variant on the second allele. In addition, the missense variant may lead to an unstable protein, as overall only 20% of the MYBPC3 protein remain detectable in affected cardiac tissue compared to control tissue. In conclusion, in patients with early disease onset and atypical clinical course, biallelic inheritance or more complex variants including copy number variations and de novo mutations should be considered. In addition, the pathogenic consequence of variants may differ in heterozygous versus compound heterozygous state.

KEYWORDS:

MYBPC3; MYH7; biallelic mutation; haploinsufficiency; left ventricular noncompaction cardiomyopathy

PMID:
30924982
DOI:
10.1002/humu.23757

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