Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing

Dellefave‐Castillo, Lisa; Cirino, Allison L.; Callis, Thomas E.; Esplin, Edward D.; Garcia, John; Hatchell, Kathryn E.; Johnson, Britt; Morales, Ana; Regalado, Ellen S.; Rojahn, Susan; Vatta, Matteo; Nussbaum, Robert L.; McNally, Elizabeth M.

doi:10.1001/jamacardio.2022.2455

Cited by 45 publications

(36 citation statements)

References 65 publications

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“…Focused on genes associated with IAS (no more than 20 major genes -ACTC1, DSC2, DSG2, DSP, HCN4, FLNC, KCNH2, KCNQ1, LMNA, MYBPC3, MYH7, PKP2, PLN, RyR2, SCN5A, TNNI3, and TTN-, and no more than 100, including minor ones) (7), the technical approach to screen a large number of genes is not the limitation to date. It is widely accepted that increasing the number of genes imply a greater number of rare variants, remaining the most part without a conclusive role in IAS; however, a recent study has suggested that combined cardiomyopathy and arrhythmia genetic testing is able to identify a 10.9% gain in genetic diagnoses that would have been missed if testing had been limited to genes associated with a single cardiomyopathy or arrhythmia panel of genes (79,80). If clinical evaluation is included in genetic diagnosis, the diagnostic yield of molecular autopsy increases to nearly 35% (81).…”

Section: Genetic Analysis/interpretationmentioning

confidence: 99%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

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In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim’s relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

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Section: Genetic Analysis/interpretationmentioning

confidence: 99%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

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“…As more genes have been identified, genetic testing yielding positive results for pathogenic mutations have been increasing. These diagnostic yields can potentially be further increased by also incorporating genetic testing for genes known to cause heritable arrhythmias with cardiomyopathy testing (14). Table 2 summarizes certain genetic syndromes with associated cardiomyopathies, and gene-targeted therapies.…”

Section: Genetic Basis Of Diseasementioning

confidence: 99%

Narrative review of pediatric heart failure in the age of precision medicine

Valikodath¹,

Godown²,

Sheybani³

2023

Transl Pediatr

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Background and Objective: Improvement in the affordability and convenience of genetic testing has rapidly expanded the understanding of the mechanistic causes of various pediatric cardiomyopathies.Concurrently, new therapies are being developed to better-target specific pathologies as opposed to classic therapies that treat the maladaptive processes of chronic heart failure. This review will discuss the advances in genetic testing and specific therapies that have been shown to benefit or potentially benefit genetically distinct subsets of the pediatric population with heart failure or at risk of developing heart failure.Methods: We undertook a comprehensive database search (January 2000-August 2022) of PubMed, utilizing terms 'pediatric', 'cardiomyopathy', 'heart failure', 'genetics', and 'precision medicine'. Additional notable studies were obtained from ClinicalTrials.gov. Studies published in English that examine genetic basis and treatment modalities of pediatric heart failure.

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“…Although immense progress has been made in elucidating the genetic determinants of HCM, much remains to be explored including genetic-, environmental- and epigenetic factors influencing disease penetrance and expressivity. Also, the rapid integration of genetic testing into everyday clinical practice has resulted in the identification of a large number of variants of uncertain significance, which cannot be acted upon clinically 10,13,14 . This issue is more evident in underrepresented populations, who are more likely to receive inconclusive genetic testing results, compared to well-studied European-ancestry HCM patients 15 .…”

Section: Introductionmentioning

confidence: 99%

Influence of ethnicity and consanguinity on the genetic architecture of Hypertrophic Cardiomyopathy: insights from an understudied population

Allouba

Walsh

Afify

et al. 2022

Preprint

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Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition characterized by phenotypic heterogeneity that could partly be explained by the variability in genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. Here, we leverage ancestry-matched Egyptian patients (n=514) and deeply-phenotyped controls (n=400) to accurately define the genetic architecture of HCM. We also compare HCM variation between Egyptian and predominantly European patients to identify genetic features unique to consanguineous populations in Middle East and North Africa (MENA), which are likely to represent important contributors to disease. We report a higher prevalence of homozygous variants in Egyptian patients (4.1% vs 0.1%, p-value=2x10-7), with variants in the minor HCM genes MYL2, MYL3 and CSRP3 more likely to present in homozygosity than the major genes (MYH7, MYBPC3), suggesting that these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (5-fold greater than European patients), highlighting the importance of recessive inheritance/genes in consanguineous populations. Finally, significantly fewer rare variants detected in Egyptian HCM patients could be classified as (likely) pathogenic compared to Europeans (40.8% vs. 61.6%, p-value=1.6x10-5) due to the underrepresentation of MENA populations in current HCM databases. This proportion increased to 53.8% after incorporating methods that compare variant frequencies between Egyptian patients and controls. Together, our findings demonstrate that studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.

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Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing

Cited by 45 publications

References 65 publications

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Narrative review of pediatric heart failure in the age of precision medicine

Influence of ethnicity and consanguinity on the genetic architecture of Hypertrophic Cardiomyopathy: insights from an understudied population

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