Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype
Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype
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DOI：
10.1002/humu.23757
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发表时间：
2019-08-01
期刊：
影响因子：
3.9
通讯作者：
Gerull, Brenda
中科院分区：
文献类型：
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作者：
Kolokotronis, Konstantinos;Kuehnisch, Jirko;Gerull, Brenda
MYH7和MYBPC3基因中的显性突变是遗传性心肌病的常见原因，其通常在家族成员中表现出可变的表型表达和不完全遗传。双等位基因遗传是罕见的，但允许深入了解单个变体的遗传作用模式。在这里，我们提出了三例携带功能丧失（LoF）变异的复合杂合状态与MYH7或MYBPC3的错义变异导致严重的心肌病左心室致密化不全。最有可能的是，由于一个LoF等位基因导致的MYH7单倍不足仅以错义变体的复合杂合形式导致临床表型。相比之下，MYBPC3的单倍不足导致严重的早发性心室致密化不全表型，当与第二等位基因上的从头错义变体结合时，需要心脏移植。此外，错义变体可能导致不稳定的蛋白质，因为与对照组织相比，在受影响的心脏组织中总体上只有20%的MYBPC 3蛋白质保持可检测。总之，在早期发病和非典型临床病程的患者中，应考虑双等位基因遗传或更复杂的变异，包括拷贝数变异和新生突变。此外，变异体的致病后果在杂合与复合杂合状态中可能不同。
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.