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Genetics of Hereditary Heart Diseases
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Genetics of Hereditary Heart Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cardiology".

Deadline for manuscript submissions: closed (10 December 2019) | Viewed by 24740

Special Issue Editor

Dr. Philippe Charron

E-Mail Website
Guest Editor
National Referral Center for Cardiachereditary Diseases, Hôpital Pitié-Salpêtrière and Paris 6 University, 75005 Paris, France
Interests: inherited cardiac diseases; genetic basis of cardiomyopathies and translational aspects

Special Issue Information

Dear Colleagues,

Inherited cardiac diseases constitute an increasingly recognized group of diseases that represent the leading causes of sudden cardiac death and heart failure in young patients, especially those younger than forty years of age. Most prevalent diseases comprise the subgroup of cardiomyopathies, disorders with primary abnormalities in the structure and function of the myocardium, and the subgroup of channelopathies, disorders resulting from the dysfunction of cardiac ion channels. Over the last three decades, there has been tremendous progress in genetics research that has identified the molecular causes for these diseases, in more than one hundred genes, and subsequently shed light on their underlying pathways and pathophysiology. Recent knowledge also suggests there is a complex interplay between genetic architecture (rare and frequent variants) and environmental factors (such as sport, myocarditis, and drugs), with important consequences for the global understanding of these monogenic diseases as well as more common and complex diseases such as heart failure and common arrhythmias.

Meantime, genetic testing and high throughput resequencing have been developed in clinical practice in order to improve the medical management of patients and their families through personalized medicine.

Finally, the emerging challenge is the translational application of this new knowledge into the development of new therapeutics, including focused pharmacological approaches such as small molecules interacting with mutated proteins, and gene editing or gene-based approaches according to the underlying mutation specific pathophysiology.

The present Special Issue aims at presenting the most recent knowledge in the rapidly expanding field of inherited cardiac diseases. This Issue will cover various aspects in order to provide guidance to practitioners in diagnosing and treating individuals with these cardiac disorders.

Prof. Dr. Philippe Charron
Guest Editor

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Keywords

  • Heart diseases
  • Gene
  • Cardiomyopathies
  • Channelopathies
  • Predictive genetic testing
  • Sudden death
  • Arrhythmia
  • Heart failure
  • Prognosis
  • Therapy

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Published Papers (6 papers)

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Research

14 pages, 1298 KiB  
Article
Psychosocial Impact of Predictive Genetic Testing in Hereditary Heart Diseases: The PREDICT Study
by Céline Bordet, Sandrine Brice, Carole Maupain, Estelle Gandjbakhch, Bertrand Isidor, Aurélien Palmyre, Alexandre Moerman, Annick Toutain, Linda Akloul, Anne-Claire Brehin, Caroline Sawka, Caroline Rooryck, Elise Schaefer, Karine Nguyen, Delphine Dupin Deguine, Cécile Rouzier, Gipsy Billy, Krystelle Séné, Isabelle Denjoy, Bruno Leheup, Marc Planes, Jean-Michael Mazzella, Stéphanie Staraci, Mélanie Hebert, Elsa Le Boette, Claire-Cécile Michon, Marie-Lise Babonneau, Angélique Curjol, Amine Bekhechi, Rafik Mansouri, Ibticem Raji, Jean-François Pruny, Véronique Fressart, Flavie Ader, Pascale Richard, Sophie Tezenas du Montcel, Marcela Gargiulo and Philippe Charronadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(5), 1365; https://doi.org/10.3390/jcm9051365 - 6 May 2020
Cited by 13 | Viewed by 3648
Abstract
Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety [...] Read more.
Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety Inventory) in 517 adults, administered three times to the prospective cohort (PCo: n = 264) and once to the retrospective cohort (RCo: n = 253). The main motivations for undergoing PGT were “to remove doubt” and “for their children”. The level of anxiety increased between pre-test and result appointments (p <0.0001), returned to baseline after the result (PCo), and was moderately elevated at 4.4 years (RCo). Subjects with a history of depression or with high baseline anxiety were more likely to develop anxiety after PGT result (p = 0.004 and p <0.0001, respectively), whatever it was. Unfavourable changes in professional and/or family life were observed in 12.4% (PCo) and 18.7% (RCo) of subjects. Few regrets about PGT were expressed (0.8% RCo, 2.3% PCo). Medical benefit was not the main motivation, which emphasises the role of pre/post-test counselling. When PGT was performed by expert teams, the negative impact was modest, but careful management is required in specific categories of subjects, whatever the genetic test result. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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12 pages, 1969 KiB  
Article
Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants
by Rob W. Roudijk, Laurens P. Bosman, Jeroen F. van der Heijden, Jacques M. T. de Bakker, Richard N. W. Hauer, J. Peter van Tintelen, Folkert W. Asselbergs, Anneline S. J. M. te Riele and Peter Loh
J. Clin. Med. 2020, 9(2), 545; https://doi.org/10.3390/jcm9020545 - 17 Feb 2020
Cited by 15 | Viewed by 3740
Abstract
Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n [...] Read more.
Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 ± 15) and pathogenic variant carriers (55 ± 10) compared to controls (35 ± 5) (p < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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12 pages, 936 KiB  
Article
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation
by Oliver Bundgaard Vad, Christian Paludan-Müller, Gustav Ahlberg, Silje Madeleine Kalstø, Jonas Ghouse, Laura Andreasen, Stig Haunsø, Arnljot Tveit, Ahmad Sajadieh, Ingrid Elisabeth Christophersen, Jesper Hastrup Svendsen and Morten Salling Olesen
J. Clin. Med. 2020, 9(2), 372; https://doi.org/10.3390/jcm9020372 - 29 Jan 2020
Cited by 14 | Viewed by 3381
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide [...] Read more.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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16 pages, 1905 KiB  
Article
Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes
by Maria Franaszczyk, Grazyna Truszkowska, Przemyslaw Chmielewski, Malgorzata Rydzanicz, Joanna Kosinska, Tomasz Rywik, Anna Biernacka, Mateusz Spiewak, Grazyna Kostrzewa, Malgorzata Stepien-Wojno, Piotr Stawinski, Maria Bilinska, Pawel Krajewski, Tomasz Zielinski, Anna Lutynska, Zofia T. Bilinska and Rafal Ploski
J. Clin. Med. 2020, 9(2), 370; https://doi.org/10.3390/jcm9020370 - 29 Jan 2020
Cited by 12 | Viewed by 3696
Abstract
The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was [...] Read more.
The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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13 pages, 1535 KiB  
Article
A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia
by Maria Donata Di Taranto, Carola Giacobbe, Alessio Buonaiuto, Ilenia Calcaterra, Daniela Palma, Giovanna Maione, Gabriella Iannuzzo, Matteo Nicola Dario Di Minno, Paolo Rubba and Giuliana Fortunato
J. Clin. Med. 2020, 9(1), 219; https://doi.org/10.3390/jcm9010219 - 14 Jan 2020
Cited by 22 | Viewed by 4267
Abstract
Homozygous familial hypercholesterolemia (HoFH), the severest form of familial hypercholesterolemia (FH), is characterized by very high LDL-cholesterol levels and a high frequency of coronary heart disease. The disease is caused by the presence of either a pathogenic variant at homozygous status or of [...] Read more.
Homozygous familial hypercholesterolemia (HoFH), the severest form of familial hypercholesterolemia (FH), is characterized by very high LDL-cholesterol levels and a high frequency of coronary heart disease. The disease is caused by the presence of either a pathogenic variant at homozygous status or of two pathogenic variants at compound heterozygous status in the LDLR, APOB, PCSK9 genes. We retrospectively analyzed data of 23 HoFH patients (four children and 19 adults) identified during the genetic screening of 724 FH patients. Genetic screening was performed by sequencing FH causative genes and identifying large rearrangements of LDLR. Among the HoFH patients, four out of 23 (17.4%) were true homozygotes, whereas 19 out of 23 (82.6%) were compound heterozygotes for variants in the LDLR gene. Basal LDL-cholesterol was 12.9 ± 2.9 mmol/L. LDL-cholesterol levels decreased to 7.2 ± 1.8 mmol/L when treated with statin/ezetimibe and to 5.1 ± 3.1 mmol/L with anti-PCSK9 antibodies. Homozygous patients showed higher basal LDL-cholesterol and a poorer response to therapy compared with compound heterozygotes. Since 19 unrelated patients were identified in the Campania region (6,000,000 inhabitants) in southern Italy, the regional prevalence of HoFH was estimated to be at least 1:320,000. In conclusion, our results revealed a worse phenotype for homozygotes compared with compound heterozygotes, thereby highlighting the role of genetic screening in differentiating one genetic status from the other. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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15 pages, 1050 KiB  
Article
Incidence of Cardiovascular Disease in Patients with Familial Hypercholesterolemia Phenotype: Analysis of 5 Years Follow-Up of Real-World Data from More than 1.5 Million Patients
by Luís Masana, Alberto Zamora, Núria Plana, Marc Comas-Cufí, Maria Garcia-Gil, Ruth Martí-Lluch, Anna Ponjoan, Lia Alves-Cabratosa, Roberto Elosua, Jaume Marrugat, Irene R. Dégano and Rafel Ramos
J. Clin. Med. 2019, 8(7), 1080; https://doi.org/10.3390/jcm8071080 - 23 Jul 2019
Cited by 39 | Viewed by 5422
Abstract
In the statin era, the incidence of atherosclerotic cardiovascular diseases (ASCVD) in patients with familial hypercholesterolemia (FH) has not been updated. We aimed to determine the incidence of ASCVD in patients with FH-phenotype (FH-P) and to compare it with that of normal low-density [...] Read more.
In the statin era, the incidence of atherosclerotic cardiovascular diseases (ASCVD) in patients with familial hypercholesterolemia (FH) has not been updated. We aimed to determine the incidence of ASCVD in patients with FH-phenotype (FH-P) and to compare it with that of normal low-density lipoprotein cholesterol (LDL-C) patients. We performed a retrospective cohort study using the Database of the Catalan primary care system, including ≥18-year-old patients with an LDL-C measurement. From 1,589,264 patients available before 2009, 12,823 fulfilled FH-P criteria and 514,176 patients were normolipidemic (LDL-C < 115 mg/dL). In primary prevention, patients with FH-P had incidences of ASCVD and coronary heart disease (CHD) of 14.9/1000 and 5.8/1000 person-years, respectively, compared to 7.1/1000 and 2.1/1000 person-years in the normolipidemic group. FH-P showed hazard ratio (HR) of 7.1 and 16.7 for ASCVD and CHD, respectively, in patients younger than 35 years. In secondary prevention, patients with FH-P had incidences of ASCVD and CHD of 89.7/1000 and 34.5/1000 person-years, respectively, compared to 90.9/1000 and 28.2/1000 person-years in the normolipidemic group (HR in patients younger than 35 years: 2.4 and 6.0). In the statin era, FH-P remains associated with high cardiovascular risk, compared with the normolipidemic population. This excess of risk is markedly high in young individuals. Full article
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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