Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy

Abstract

Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single‐nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models were applied to identify the probability of cardiomyopathy type as it related to the number of nsSNVs in cardiomyopathy genes. The probability of having DCM significantly increased as the number of cardiomyopathy gene nsSNVs per person increased. The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter for individuals carrying a DCM diagnosis, but not for those with HCM. Resampling was used to identify genes with aberrant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions Participants with DCM had more nsSNVs per person in cardiomyopathy genes than participants with HCM. The nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support the concept that increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity.

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

“…This could be because the heritability estimation was underpowered based on the low prevalence (0.25%) with a low number of cases (2,993 cases) and because the disease has heterogeneous subtypes, including dilated and hypertrophic cardiomyopathy, with different genetic causes. 10 Cell Genomics 2, 100192, October 12, 2022 5 Article ll OPEN ACCESS Identified associations were largely shared across biobanks. The lead variants at 95% (n = 476) of the 500 genomewide loci did not show evidence for heterogeneity in effect sizes across different datasets (per biobank and ancestry) (Table S7) with a p value for Cochran's Q test R1/500, despite biobanks differing in many aspects, as discussed above.…”

A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve

“…83 Even in severe cardiac diseases that manifest in children or young adults (ie, congenital heart disease and cardiomyopathies) and may appear to have a single Mendelian genetic basis, phenotypic expression is influenced by multiple DNA variants, suggesting that these diseases are oligogenic 84 or polygenic. 85 This implies that the combined action of genetic modifiers can have a major effect on the expression of a cardiac disease phenotype, 3,86 making it difficult to define its genetic pathogenesis.…”

“…Cardiomyopathies were initially thought to be monogenic disorders; however, phenotypic expressivity and penetrance have been found to be affected by variable presentation within a family with the same mutation, 1 the influence of multiple genetic variants and their epistatic relationships, and epigenetic and environmental factors. 2,3 Left ventricular noncompaction (LVNC) is the third most common cardiomyopathy (prevalence, 0.05% 4 ) and is characterized by the presence of excessive trabeculae with deep recesses in the left ventricle. 5,6 Trabeculae are endocardial cell-covered cardiomyocyte bundles in the vertebrate ventricle that facilitate oxygen and nutrient exchange.…”

Phenotype variation of hypertrophic cardiomyopathy in carriers of the p.Arg870His pathogenic variant in the MYH7 gene

“…[55] при проведении GWAS были установлены 12 локусов, ассоциированных с гипертрофической кардиомиопатий. При этом такие однонуклеотидные полиморфизмы оказывают влияние на тяжесть течения ГКМП у носителей мутаций в генах саркомерных белков [55,60].…”