Year: 2017
Type: editorial
Abstract: A rrhythmogenic cardiomyopathy (AC) is an enigmatic inherited cardiomyopathy characterized by fibro-fatty replacement of cardiac myocytes and ventricular arrhythmias.[1][2][3] When affecting predominantly the right ventricle, this disease is referred as arrhythmogenic right ventricular cardiomyopathy.The prevalence of AC in the general population has been estimated in a range from 1 in 2000 to 1 in 5000 individuals.Clinically, it is characterized by palpitations, syncope, and sudden cardiac death because of ventricular arrhythmias.This cardiomyopathy is a major cause of sudden cardiac death in the young people and in athletes.[1][2][3] To date, there is no effective pharmacological therapy for this deadly cardiac disease, which may require implantable defibrillators and heart transplantation at the advanced stage.4 AC is a hereditary autosomal dominant disease with reduced penetrance and variable clinical expression.Thus far, 5 causal genes have been identified, all coding for desmosomal proteins.5 These known causal desmosomal genes are plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and democollin-2 (DSC2).Desmosomal proteins are structural proteins important for cell-cell attachment and communication.PKP2 is the most common causal gene for AC, accounting for up to 43% of the cases.[6][7][8] Most of PKP2 mutations are loss-offunction mutations resulting in reduced expression of PKP2 (haploinsufficiency 6,9 ).Atypical forms of AC are caused by mutations in nondesmosomal genes, such as transforming growth factor-β-3 (TGFβ3), cardiac ryanodine receptor (RYR2), transmembrane protein 43 (TMEM43), and lamin A/C (LMNA).Current diagnostic strategies rely on next-generation DNA sequencing that has poor sensitivity for genomic deletions and identifies causative variants in only ≈50% of the AC cases, leaving half of cases with unknown genetic cause.To address the possibility of genomic mutations, Pilichou et al 10 turned to multiplex ligation-dependent probe amplification to quantify genomic deletions in 160 patients with AC who had negative next-generation DNA sequencing testing for the expected AC genes.The human genome consists of >3 billion base pairs of DNA packaged into 2 sets of 23 chromosomes of which one set of chromosomes is inherited from each parent.These chromosomes contain DNA sequences encoding for ≈30 000 genes.In general, each gene is presumed to be present in 2 copies in a genome.However, recent studies have revealed different copy number variants (CNVs) of large DNA segments ranging in size from kilobases to megabases as the source of genetic diversity in the general population.Since then, several research groups have identified CNVs of large segments of chromosomes that encompass genes and that are associated with diseases.[11][12][13][14] CNVs can cause diseases through different mechanisms: variation of gene dosage through insertions or deletions (1), unmasking of a recessive allele alters the gene expression through inversions, deletions, or trans- Unraveling Missing Genes and Missing Inheritance in Arrhythmogenic Cardiomyopathy
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2766300056