Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular non-compaction phenotype

TY - JOUR

T1 - Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular non-compaction phenotype

AU - Kolokotronis, Konstantinos

AU - Kühnisch, Jirko

AU - Klopocki, Eva

AU - Dartsch, Josephine

AU - Rost, Simone

AU - Huculak, Cathleen

AU - Mearini, Giulia

AU - Störk, Stefan

AU - Carrier, Lucie

AU - Klaassen, Sabine

AU - Gerull, Brenda

PY - 2019

Y1 - 2019

N2 - 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 variant in a compound heterozygous state with a missense variant in either MYH7 or MYBPC3 leading to severe cardiomyopathy with left ventricular non-compaction. Most likely, MYH7 haploinsufficiency due to one loss-of-function 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 non-compaction 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 CNVs and de novo mutations should be considered. Additionally, the pathogenic consequence of variants may differ in heterozygous versus compound heterozygous state. This article is protected by copyright. All rights reserved.

AB - 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 variant in a compound heterozygous state with a missense variant in either MYH7 or MYBPC3 leading to severe cardiomyopathy with left ventricular non-compaction. Most likely, MYH7 haploinsufficiency due to one loss-of-function 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 non-compaction 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 CNVs and de novo mutations should be considered. Additionally, the pathogenic consequence of variants may differ in heterozygous versus compound heterozygous state. This article is protected by copyright. All rights reserved.

U2 - 10.1002/humu.23757

DO - 10.1002/humu.23757

M3 - SCORING: Journal article

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

ER -