Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

Abstract

This is the first of 2 review papers on genetics and genomics appearing as part of the series on "omics." Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.

Keywords: cardiomyopathy; mutation; noncoding RNA.

Figure 1. Effect Size of GVs and Clinical Phenotype

The population frequency of GVs is depicted against their effect sizes. Rare variants are more likely to impart larger effect sizes than common variants, which typically impart small or clinically negligible effect sizes. Rare variants with very large effect sizes cause single-gene diseases, multiple uncommon variants with moderate effect sizes cause oligogenic diseases, and a very large number of common variants are responsible for complex phenotypes.

Figure 2. Common Forms of Primary Cardiomyopathies

The diagram illustrates common forms of primary cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restricted cardiomyopathy (RCM). A subset of DCM predominantly manifests with ventricular arrhythmias and is referred to as arrhythmogenic DCM. The latter category, along with classic ARVC, encompasses arrhythmogenic cardiomyopathy (AC).

Figure 3. Schematic Illustration of Pathogenesis of HCM

Mutations in genes encoding sarcomere proteins impart a diverse array of initial defects, such as altered myofibrillar mechanical or biochemical functions, leading to expression and activation of trophic and mitotic pathways, including cardiac hypertrophy and interstitial fibrosis. HCM = hypoertrophic cardiomyopathy.

Figure 4. Fibro-Adipocytes Replacing Cardiac Myocytes in ARVC

The photomicrograph illustrates thin myocardial sections stained with Masson trichrome, showing excess adipocytes and fibrosis (blue). The pathognomonic feature of classic ARVC is excess fibro-adipocytes replacing cardiac myocytes predominantly in the right ventricle. ARVC = arrhythmogenic right ventricular cardiomyopathy.

Figure 5. Pathogenesis of AC

The diagram illustrates the mechanisms involved in the pathogenesis of cardiac dysfunction, arrhythmias, and excess fibro-adipocytes in AC. Mutations impair the mechanical integrity of the intercalated discs and lead to cardiac dysfunction. Mechanical dysfunction also activates mechanosensitive signal transduction pathways, leading to suppression of gene expression through the YAP-TEAD and CTNNB1 (β-catenin)-TCF7L2 pathways. A transcriptional switch in a subset of fibro-adipocyte progenitor cells results in their differentiation to fibro-adipocytes, and also contributes to cardiac dysfunction. AC = arrhythmogenic cardiomyopathy; MAPK = mitogen-activated protein kinase.

Central Illustration. Basic Structure of the Genome

The nuclear genome is organized into chromosomes and wrapped in histone proteins, condensed into chromatin, and arranged in segments referred to nucleosomes. Histone modifications affect the chromatin state and gene expression. Each gene contains a 5′ regulatory or untranslated region (5′ UTR) where the transcription factors bind and initiate transcription of the primary transcript. Each gene also contains exons and the intervening regions referred to as introns. Splicing machinery binds to exon-intron boundaries and splices out introns from the coding transcript, referred to as messenger RNA (mRNA). The first coding exon contains the signal for initiation of translation, namely ATG, and the last coding exon contains a translation termination codon, such as TAG (UAG in the mRNA). The 3′ regulatory region or 3′ UTR contains 1 or more polyadenylation signals, which signal for adding a poly-A tail to the mRNA. It is also the binding site for microRNAs (miRNAs). MicroRNAs and long noncoding RNAs (lncRNAs) are transcribed from introns or intergenic regions. SNP = single-nucleotide polymorphism