Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification

Meulen, Marijke H van der; Herkert, Johanna C.; Boer, Susanna L. den; Sarvaas, Gideon J. du Marchie; Blom, Nico A.; Harkel, Arend D J Ten; Breur, Johannes M.P.J.; Rammeloo, Lukas A. J.; Tanke, Ronald B.; Marcelis, Carlo; Laar, Ingrid M.B.H. van de; Verhagen, Judith M.A.; Deprez, Ronald Lekanne; Barge-Schaapveld, Daniela Q.C.M.; Baas, Annette F.; Sammani, Arjan; Christiaans, Imke; Tintelen, Peter van; Dalinghaus, Michiel

doi:10.1161/circgen.120.002981

Cited by 8 publications

(8 citation statements)

References 57 publications

(72 reference statements)

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“…A recent GWAS meta-analysis concluded that this kinase holds a direct phenotypic effect in the heart, causing reduced left ventricular systolic function and cardiomyocyte cell cycle arrest [39]. An in-vivo model of CDKN1A knockout mice developed cardiac hypertrophy and HF [51]. A phenome-wide association study (PheWAS; comparing a trait in individuals with or without a reported clinical outcome) further identified the CDKN1A locus as significantly associated with HCM and ECG traits (PR interval and QRS duration) [52].…”

Section: Common Dna Variants Associated With Hypertrophic Cardiomyopathymentioning

confidence: 99%

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

Mukhopadhyay,

Dixit,

Khanom

et al. 2024

J. of Cardiovasc. Trans. Res.

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Heart failure (HF) remains a major cause of mortality and morbidity worldwide. Understanding the genetic basis of HF allows for the development of disease-modifying therapies, more appropriate risk stratification, and personalised management of patients. The advent of next-generation sequencing has enabled genome-wide association studies; moving beyond rare variants identified in a Mendelian fashion and detecting common DNA variants associated with disease. We summarise the latest GWAS and rare variant data on mixed and refined HF aetiologies, and cardiomyopathies. We describe the recent understanding of the functional impact of titin variants and highlight FHOD3 as a novel cardiomyopathy-associated gene. We describe future directions of research in this field and how genetic data can be leveraged to improve the care of patients with HF. Graphical Abstract

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Section: Common Dna Variants Associated With Hypertrophic Cardiomyopathymentioning

confidence: 99%

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

Mukhopadhyay,

Dixit,

Khanom

et al. 2024

J. of Cardiovasc. Trans. Res.

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“…In a subcohort of more complex cases, 26/46 (57%) received a change in management and risk stratification ( 25 ). Pediatric DCM cases with a pathogenic or likely pathogenic variant had 2.8-times increased risk of death or heart transplant, suggesting the importance of genetic testing for predicting clinical outcomes ( 26 ). In 2021, Murdock, et al reported on a next-generation sequencing (NGS)-based genetic testing panel that returned results with clinical management implications for 32% of patients seen in institutionally affiliated adult cardiology clinics ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases

Longoni,

Bhasin,

Ward

et al. 2023

Front. Cardiovasc. Med.

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BackgroundCardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting major cardiac adverse events recommend genetic testing for inherited cardiovascular conditions such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), hereditary amyloidosis, and familial hypercholesterolemia (FH); however, little is known about how consistently practitioners order genetic testing for these conditions in routine clinical practice. This study aimed to assess the adoption of guideline-directed genetic testing for patients diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH.MethodsThis retrospective cohort study captured real-world evidence of genetic testing from ICD-9-CM and ICD-10-CM codes, procedure codes, and structured text fields of de-identified patient records in the Veradigm Health Insights Ambulatory EHR Research Database linked with insurance claims data. Data analysis was conducted using an automated electronic health record analysis engine. Patient records in the Veradigm database were sourced from more than 250,000 clinicians serving over 170 million patients in outpatient primary care and specialty practice settings in the United States and linked insurance claims data from public and private insurance providers. The primary outcome measure was evidence of genetic testing within six months of condition diagnosis.ResultsBetween January 1, 2017, and December 31, 2021, 224,641 patients were newly diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH and included in this study. Substantial genetic testing care gaps were identified. Only a small percentage of patients newly diagnosed with DCM (827/101,919; 0.8%), HCM (253/15,507; 1.6%), LQTS (650/56,539; 1.2%), hereditary amyloidosis (62/1,026; 6.0%), or FH (718/49,650; 1.5%) received genetic testing.ConclusionsGenetic testing is underutilized across multiple inherited cardiovascular conditions. This real-world data analysis provides insights into the delivery of genomic healthcare in the United States and suggests genetic testing guidelines are rarely followed in practice.

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“…Previous studies have suggested that 27% to 54% of iDCM cases have a genetic component. 5–8 Common mutations in genes related to sarcomere structure (such as MYH7 , MYBPC3 , and TNNT2 ), nuclear envelope (such as LMNA ), and cytoskeleton (such as DES and DMD ) have been described previously. 4–8 Increased widespread genetic testing abilities have begun to help identify novel classes of genes suspected to be responsible for iDCM, greatly expanding our understanding of the pathogenesis of this condition.…”

mentioning

confidence: 98%

“…nfantile dilated cardiomyopathy (iDCM) is a rare condition with multiple pathogeneses that results in substantial morbidity and mortality. [1][2][3][4][5] Of the studied infantile cardiomyopathies, dilated cardiomyopathy is the most prevalent, responsible for ≈50% of infantile/pediatric cardiomyopathy cases. 2 Such cases are particularly difficult to manage, and many will necessitate heart transplant as the final management approach.…”

mentioning

confidence: 99%

Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy

et al. 2023

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BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN , the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient’s condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.

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Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification

Cited by 8 publications

References 57 publications

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases

Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy

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