Introduction
Cardiovascular disease (CVD) stands as a predominant health concern, impacting a staggering 80,000,000 individuals in the United States alone. This category encompasses a spectrum of conditions ranging from myocardial infarction to congenital heart disease, many of which exhibit hereditary traits. Extensive research efforts have been dedicated to unraveling the genetic underpinnings and specific DNA sequence variations responsible for this heritability. Remarkably, activating mutations in oncogenes have been identified across a diverse array of non-malignant disorders.
In virtually all these disorders, inherited DNA sequence variations contribute significantly to disease risk. For instance, within the general population, a parental history of premature atherosclerotic CVD imparts approximately a 3.0-fold increase in cardiovascular disease risk to their offspring. The precise extent of the role played by inheritance, however, varies across different diseases and is influenced by factors such as the age of disease onset and the specific subtype of the disease.
Other noteworthy examples within the realm of CVD include long QT syndrome, severe hypercholesterolemia, Mendelian forms of hypertension, Marfan’s syndrome, as well as various forms of congenital heart disease, including septal defects and valve defects. (Kathiresan, 2012).
Applications
Linkage studies entail the identification and recruitment of families displaying distinctive and frequently severe phenotypes. The process involves isolating a chromosomal segment that co-segregates with the disease status within the family, followed by the precise localization of the causal gene and mutation within the linked segment. Certain cardiovascular diseases (CVD) manifest a straightforward inheritance pattern indicative of a solitary causal gene exerting a substantial impact on the phenotype. In numerous instances of Mendelian forms of CVD, the application of direct DNA sequencing and/or linkage analysis has proven effective in elucidating the causal gene and associated mutation (Kathiresan, 2012).
The majority of cardiovascular diseases (CVDs) exhibit a discernible genetic element in their etiologies. With the exception of exceedingly uncommon Mendelian Cardiovascular cases characterized by strictly monogenic dominant inheritance, a considerable portion of patients is recognized to manifest polygenic/multifactorial forms. In these instances, the pathology arises from the interaction of two or more genetic defects situated in either the same or different genes, along with influential environmental factors.
Next-generation sequencing (NGS) has afforded the capability for concurrent analysis of a substantial number of genes, potentially enhancing our understanding of the pathogenesis of intricate diseases like cardiovascular disease (CVD). This approach also proves valuable for uncovering rare variants in smaller familial cohorts. Examples of Mendelian disorders within cardiovascular medicine encompass familial hypercholesterolemia, hypertrophic and familial dilated cardiomyopathies, as well as channelopathies such as Brugada and long QT syndrome. In contrast, prevalent cardiovascular diseases encountered in clinical practice, such as coronary artery disease (CAD) and stroke, are characterized by intricate gene–gene and gene–environmental interactions. Molecular genetic testing, initially employed as a research tool, has recently transitioned into clinical diagnostic applications, offering the potential for more personalized and informative counseling for affected families (Kalayinia, 2018).
Benefits
In the realm of cardiovascular medicine, next-generation sequencing (NGS) has demonstrated efficacy in uncovering novel causative mutations and diagnosing Mendelian diseases characterized by a singular variant in a single gene. Mendelian cardiovascular diseases encompass familial hypercholesterolemia, cardiomyopathies, primary arrhythmias, congenital heart disease (CHD), and thoracic aortic aneurysms and dissections (TAAD). Furthermore, NGS is gaining prominence in common cardiovascular diseases (CVDs). Unlike genome-wide association studies (GWASs), which furnish solely known single nucleotide polymorphism (SNP) data, NGS can yield a broader dataset, encompassing both common and rare variants, indels (insertions and deletions), and copy-number variations (CNVs) (Kalayinia, 2018).
While somewhat constrained, the identification of causative genes and mutations associated with cardiomyopathies bears prognostic implications. Specifically, certain gene variants implicated in cardiomyopathies are associated with early-onset disease manifestation, an overall unfavorable prognosis, or an elevated risk of sudden cardiac death. An illustrative instance of the impact of Next-Generation Sequencing (NGS) on elucidating the genetic landscape of cardiomyopathies is the identification of a truncating mutation in the TTN (titin) gene as a primary contributor to dilated cardiomyopathy (DCM). Since 1999, mutations in TTN, responsible for encoding the colossal muscle filament titin, have been identified as causative factors in familial DCM.
Genetic testing is undergoing a transformative phase in disease management, propelled by the distinctive capabilities of Next-Generation Sequencing (NGS) techniques. These techniques play a pivotal role in identifying causative mutations associated with frequently fatal conditions and in screening at-risk relatives. In a groundbreaking effort in 2017, Chae et al introduced a targeted multi-gene NGS custom panel comprising 13 genes linked to long QT syndrome (LQTS), utilizing the Ion PGM platform. The system was successfully validated for routine application in the clinical genetic diagnosis of LQTS and other genetic diseases.
Emerging technologies, exemplified by NGS, have already made significant strides in pinpointing causative mutations in congenital heart diseases (CHDs). This progress holds the promise of substantially advancing our understanding of the genetic factors contributing to CHD (Kalayinia, 2018).
Sample Specifications
Specimens must be provided in the form of Whole Blood, with a preference for 2 EDTA tubes, or alternatively, as Buccal Swab or Extracted DNA.