Figure - available from: Frontiers in Cardiovascular Medicine
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Schematic representation of the workflow used for appropriate classification and interpretation of the genetic variants in clinical practice (details in text). 1000G, 1,000 Genomes; ESP6500, NHLBI Exome Sequencing Project; ExAC, Exome Aggregation Consortium; gnomAD, Genome Aggregation Database; ClinVar, Clinical Variation database; OMIM, Online Mendelian Inheritance in Man; LSDBs, Locus Specific Databases; HGVS, Human Genome Variation Society; HPO, Human Phenotype Ontology; ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; ClinGen, Clinical Genome Resource; VCEP, Variant Curation Expert Panel.
Source publication
Inherited cardiovascular diseases are highly heterogeneous conditions with multiple genetic loci involved. The application of advanced molecular tools, such as Next Generation Sequencing, has facilitated the genetic analysis of these disorders. Accurate analysis and variant identification are required to maximize the quality of the sequencing data....
Citations
... 50 In RCM, TTE findings of diastolic dysfunction with atrial enlargement could be observed, but cardiac magnetic resonance could be of greater diagnostic value with high specificity to differentiate from other mimics, such as constrictive pericarditis. 51,52 As it currently stands, certain risk factors have been discussed in the literature to help stratify patients. In HCM, for example, a prior aborted cardiac arrest, nonsustained ventricular tachycardia, unexplained syncope, LV thickness >30 mm, abnormal exercise blood pressure, and family history of premature sudden cardiac death are all major risk factors for sudden cardiac death. ...
... Patients with these variants are often associated with debilitating outcomes, requiring implantable cardiac defibrillators to prevent sudden cardiac death. 52 Yet, almost 55% of pathogenic variants in DCM are idiopathic and may overlap with variants causing ACM, highlighting the need to implement better classification in a genotypic setting. 55 Similarly, with HCM, the common genes involved are MYH7 and MYBPC3, which have a high degree of major adverse cardiovascular effects. ...
Background Hereditary cardiomyopathies are commonly occurring myocardial conditions affecting heart structure and function with a genetic or familial association, but the etiology is often unknown. Cardiomyopathies are linked to significant mortality, requiring robust risk stratification with genetic testing and early diagnosis.
Hypothesis We hypothesized that health care disparities exist in genetic testing for hereditary cardiomyopathies within clinical practice and research studies.
Methods In a narrative fashion, we conducted a literature search with online databases such as PubMed/MEDLINE, Google Scholar, EMBASE, and Science Direct on papers related to hereditary cardiomyopathies. A comprehensive analysis of findings from articles in English on disparities in diagnostics and treatment was grouped into four categories.
Results Racial and ethnic disparities in research study enrollment and health care delivery favor White populations and higher socioeconomic status, resulting in differences in the development and implementation of effective genetic screening. Such disparities have shown to be detrimental, as minorities often suffer from disease progression to heart failure and sudden cardiac death. Barriers related to clinical genetic testing included insurance-related issues and health illiteracy. The underrepresentation of minority populations extends to research methodologies, as testing in ethnic minorities resulted in a significantly lower detection rate and diagnostic yield, as well as a higher likelihood of misclassification of variants.
Conclusions Prioritizing minority-based participatory research programs and screening protocols can address systemic disparities. Diversifying research studies can improve risk stratification strategies and impact clinical practice.
In the last decade, an incredible improvement has been made in elucidating the genetic bases of cardiomyopathies. Here we report the impact of either the European Society of Cardiology (ESC) guidelines or the use of whole exome sequencing (WES) in terms of a number of variants of uncertain significance (VUS) and missed diagnoses in a series of 260 patients affected by inherited cardiac disorders. Samples were analyzed using a targeted gene panel of 128 cardiac‐related genes and/or WES in a subset of patients, with a three‐tier approach. Analyzing (i) only a subset of genes related to the clinical presentation, strictly following the ESC guidelines, 20.77% positive test were assessed. The incremental diagnostic rate for (ii) the whole gene panel, and (iii) the WES was 4.71% and 11.67%, respectively. The diverse analytical approaches increased the number of VUSs and incidental findings. Indeed, the use of WES highlights that there is a small percentage of syndromic conditions that standard analysis would not have detected. Moreover, the use of targeted sequencing coupled with “narrow” analytical approach prevents the detection of variants in actionable genes that could allow for preventive treatment. Our data suggest that genetic testing might aid clinicians in the diagnosis of inheritable cardiac disorders.
