Publications by authors named "J Peter van Tintelen"

186 Publications

P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy.

J Cell Mol Med 2021 Feb 18. Epub 2021 Feb 18.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy is a possible mechanism of disease development. The objective of this study was to investigate the distribution in the myocardium of such aggregates in relation to specific pathogenic genetic mutations in cardiomyopathy hearts. Hearts from 32 genetic cardiomyopathy patients, 4 non-genetic cardiomyopathy patients and 5 controls were studied. Microscopic slices from an entire midventricular heart slice were stained for p62 (sequestosome-1, marker for aggregated proteins destined for autophagy). The percentage of cardiomyocytes with p62 accumulation was higher in cardiomyopathy hearts (median 3.3%) than in healthy controls (0.3%; P < .0001). p62 accumulation was highest in the desmin (15.6%) and phospholamban (7.2%) groups. P62 accumulation was homogeneously distributed in the myocardium. Fibrosis was not associated with p62 accumulation in subgroup analysis of phospholamban hearts. In conclusion, accumulation of p62-positive protein aggregates is homogeneously distributed in the myocardium independently of fibrosis distribution and associated with desmin and phospholamban cardiomyopathy. Proteotoxic protein accumulation is a diffuse process in the myocardium while a more localized second hit, such as local strain during exercise, might determine whether this leads to regional myocyte decay.
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http://dx.doi.org/10.1111/jcmm.16388DOI Listing
February 2021

Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features.

Circ Genom Precis Med 2021 Feb 10. Epub 2021 Feb 10.

Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin & Cardiomyopathies Unit, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital & Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy & Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.

- Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants, in the non-desmosomal cadherin 2 (), a novel genetic substrate of ACM. - A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of -positive probands, and clinical evaluation was assessed. - Genetic screening of led to the identification of 7 rare variants: five, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and/or sudden cardiac death occurred in 5/9 (56%). - In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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http://dx.doi.org/10.1161/CIRCGEN.120.003097DOI Listing
February 2021

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status.

Neth Heart J 2021 Feb 2. Epub 2021 Feb 2.

Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited.

Aim: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression.

Methods: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death).

Results: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects.

Conclusion: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.
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http://dx.doi.org/10.1007/s12471-021-01539-wDOI Listing
February 2021

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium.

Neth Heart J 2021 Feb 2. Epub 2021 Feb 2.

Department of Cardiology, Division Heart and Lungs, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.
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http://dx.doi.org/10.1007/s12471-021-01542-1DOI Listing
February 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
February 2021

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.

Circ Arrhythm Electrophysiol 2021 Jan 9;14(1):e008509. Epub 2020 Dec 9.

Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD.

Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping.

Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism.

Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
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http://dx.doi.org/10.1161/CIRCEP.120.008509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834666PMC
January 2021

Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions.

Circ Genom Precis Med 2020 Oct 14;13(5):524-530. Epub 2020 Aug 14.

Department of Clinical Genetics (L.M.v.d.H., M.O.v.T., J.P.v.T., I.C.), Amsterdam UMC, University of Amsterdam.

Background: Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure.

Methods: Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible.

Results: Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0-187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives <40 years.

Conclusions: During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling.
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http://dx.doi.org/10.1161/CIRCGEN.119.002803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889286PMC
October 2020

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients.

Genes (Basel) 2020 Oct 13;11(10). Epub 2020 Oct 13.

Department of Clinical Genetics, Amsterdam UMC (location VUmc), 1081HV Amsterdam, The Netherlands.

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 and negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 ( = 4), GDF2 ( = 2), EIF2AK4 ( = 1), and TBX4 ( = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH.
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http://dx.doi.org/10.3390/genes11101191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602048PMC
October 2020

Author Correction: The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy.

Sci Rep 2020 Oct 2;10(1):16710. Epub 2020 Oct 2.

Department of Experimental Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70780-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532180PMC
October 2020

Influence of Panel Selection on Yield of Clinically Useful Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Families.

Circ Genom Precis Med 2020 Oct 16;13(5):548-550. Epub 2020 Sep 16.

Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (B.M., C.T., H.T., H.C., C.A.J.).

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http://dx.doi.org/10.1161/CIRCGEN.120.003020DOI Listing
October 2020

Strength of patient cohorts and biobanks for cardiomyopathy research.

Neth Heart J 2020 Aug;28(Suppl 1):50-56

Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.
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http://dx.doi.org/10.1007/s12471-020-01456-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419403PMC
August 2020

Desmin is essential for the structure and function of the sinoatrial node: implications for increased arrhythmogenesis.

Am J Physiol Heart Circ Physiol 2020 09 17;319(3):H557-H570. Epub 2020 Jul 17.

Center of Clinical Research and Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece.

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call "lateral intercalated disks" connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des mice. Upregulation of mRNA levels of both T-type Ca current channels, Cav3.1 and Cav3.2, in the Des myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis. The sinoatrial node exhibits high amounts of desmin and desmoplakin in structures we call "lateral intercalated disks," connecting side-by-side adjacent cardiomyocytes. These structures are diminished in desmin-deficient mouse models. Misregulation of T-type Ca current and hyperpolarization-activated cyclic nucleotide-gated K channel 1 was proved along with prolonged interatrial conduction and cardiac autonomic nervous system dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00594.2019DOI Listing
September 2020

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy.

Sci Rep 2020 06 17;10(1):9819. Epub 2020 Jun 17.

Department of Experimental Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.
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http://dx.doi.org/10.1038/s41598-020-66656-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300032PMC
June 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Authors:
Najim Lahrouchi Rafik Tadros Lia Crotti Yuka Mizusawa Pieter G Postema Leander Beekman Roddy Walsh Kanae Hasegawa Julien Barc Marko Ernsting Kari L Turkowski Andrea Mazzanti Britt M Beckmann Keiko Shimamoto Ulla-Britt Diamant Yanushi D Wijeyeratne Yu Kucho Tomas Robyns Taisuke Ishikawa Elena Arbelo Michael Christiansen Annika Winbo Reza Jabbari Steven A Lubitz Johannes Steinfurt Boris Rudic Bart Loeys M Ben Shoemaker Peter E Weeke Ryan Pfeiffer Brianna Davies Antoine Andorin Nynke Hofman Federica Dagradi Matteo Pedrazzini David J Tester J Martijn Bos Georgia Sarquella-Brugada Óscar Campuzano Pyotr G Platonov Birgit Stallmeyer Sven Zumhagen Eline A Nannenberg Jan H Veldink Leonard H van den Berg Ammar Al-Chalabi Christopher E Shaw Pamela J Shaw Karen E Morrison Peter M Andersen Martina Müller-Nurasyid Daniele Cusi Cristina Barlassina Pilar Galan Mark Lathrop Markus Munter Thomas Werge Marta Ribasés Tin Aung Chiea C Khor Mineo Ozaki Peter Lichtner Thomas Meitinger J Peter van Tintelen Yvonne Hoedemaekers Isabelle Denjoy Antoine Leenhardt Carlo Napolitano Wataru Shimizu Jean-Jacques Schott Jean-Baptiste Gourraud Takeru Makiyama Seiko Ohno Hideki Itoh Andrew D Krahn Charles Antzelevitch Dan M Roden Johan Saenen Martin Borggrefe Katja E Odening Patrick T Ellinor Jacob Tfelt-Hansen Jonathan R Skinner Maarten P van den Berg Morten Salling Olesen Josep Brugada Ramón Brugada Naomasa Makita Jeroen Breckpot Masao Yoshinaga Elijah R Behr Annika Rydberg Takeshi Aiba Stefan Kääb Silvia G Priori Pascale Guicheney Hanno L Tan Christopher Newton-Cheh Michael J Ackerman Peter J Schwartz Eric Schulze-Bahr Vincent Probst Minoru Horie Arthur A Wilde Michael W T Tanck Connie R Bezzina

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 Task Force Criteria: clinical performance and simplified practical implementation.

Europace 2020 05;22(5):787-796

Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation.

Methods And Results: We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%).

Conclusion: The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.
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http://dx.doi.org/10.1093/europace/euaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203633PMC
May 2020

The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy.

Eur Heart J 2020 04;41(14):1393-1400

Division of Cardiology, Department of Medicine, Johns Hopkins University, Carnegie 568D, 600 N. Wolfe St., Baltimore, MD 21287-0409, USA.

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiomyopathy characterized by frequent ventricular arrhythmias and progressive ventricular dysfunction. Risk of sudden cardiac death is elevated in ACM patients and can be the presenting symptom particularly in younger individuals and athletes. This review describes current understanding of the genetic architecture of ACM and molecular mechanisms of ACM pathogenesis. We consider an emerging threshold model for ACM inheritance in which multiple factors including pathogenic variants in known ACM genes, genetic modifiers, and environmental exposures, particularly exercise, are required to reach a threshold for disease expression. We also review best practices for integrating genetics-including recent discoveries-in caring for ACM families and emphasize the utility of genotype for both management of affected individuals and predictive testing in family members.
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http://dx.doi.org/10.1093/eurheartj/ehaa141DOI Listing
April 2020

Quantitative Approach to Fragmented QRS in Arrhythmogenic Cardiomyopathy: From Disease towards Asymptomatic Carriers of Pathogenic Variants.

J Clin Med 2020 Feb 17;9(2). Epub 2020 Feb 17.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508 GA Utrecht, The Netherlands.

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 ( = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis ( = 57, 17%) and control subjects ( = 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) ( < 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia ( = 0.701) at baseline or during follow-up ( = 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.
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http://dx.doi.org/10.3390/jcm9020545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073517PMC
February 2020

Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5.

Heart Rhythm 2020 06 13;17(6):945-954. Epub 2020 Feb 13.

Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; CIBERCV, Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain. Electronic address:

Background: Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the nondesmosomal gene TMEM43-endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or whether the disease is influenced by genetic or environmental factors.

Objective: The purpose of this study was to examine the phenotype, clinical course, and the impact of exercise on patients with p.S358L ARVC-5 without the Newfoundland genetic background.

Methods: We studied 62 affected individuals and 73 noncarriers from 3 TMEM43-p.S358L Spanish families. The impact of physical activity on the phenotype was also evaluated.

Results: Haplotype analysis revealed that the 3 Spanish families were unrelated to patients with ARVC-5 with the Newfoundland genetic background. Two families shared 10 microsatellite markers in a 4.9 cM region surrounding TMEM43; the third family had a distinct haplotype. The affected individuals showed a 38.7% incidence of sudden cardiac death, which was higher in men. Left ventricular involvement was common, with 40% of mutation carriers showing a left ventricular ejection fraction of <50%. Compared with noncarriers, the R-wave voltage in lead V was lower (3.2 ± 2.8 mV vs 7.5 ± 3.6 mV; P < .001) and QRS complex in right precordial leads wider (104.7 ± 24.0 ms vs 88.2 ± 7.7 ms; P = .001). A history of vigorous exercise showed a trend toward more ventricular arrhythmias only in women (P = .053).

Conclusion: ARVC-5 is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic features irrespective of geographical origin and genetic background. Our data suggest that, as in desmosomal ARVC, vigorous physical activity could aggravate the phenotype of TMEM43 mutation carriers.
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http://dx.doi.org/10.1016/j.hrthm.2020.01.035DOI Listing
June 2020

Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient.

Clin Genet 2020 05 16;97(5):723-730. Epub 2020 Jan 16.

Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.

Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
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http://dx.doi.org/10.1111/cge.13700DOI Listing
May 2020

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary.

Heart Rhythm 2019 11;16(11):e373-e407

University of Rochester Medical Center, Rochester, New York.

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
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http://dx.doi.org/10.1016/j.hrthm.2019.09.019DOI Listing
November 2019

Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy.

J Med Genet 2020 01 7;57(1):23-30. Epub 2019 Sep 7.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy.

Methods And Results: Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in . This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O) into HO. Measurement of hydroethidine oxidation showed a significant increase in O levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2.

Conclusion: Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
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http://dx.doi.org/10.1136/jmedgenet-2019-106330DOI Listing
January 2020

Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.

Circ Genom Precis Med 2019 08 6;12(8):e002467. Epub 2019 Aug 6.

Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, the Netherlands (F.H.M.v.L., R.Z., R.H.L.D., J.P.v.T., C.A.J.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with pathogenic/likely pathogenic (P/LP) variants in genes encoding the cardiac desmosomal proteins. Origin of these variants, including de novo mutation rate and extent of founder versus recurrent variants has implications for variant adjudication and clinical care, yet this has never been systematically investigated.

Methods: We identified arrhythmogenic right ventricular cardiomyopathy probands who met 2010 Task Force Criteria and had undergone genotyping that included sequencing of the desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP) from 3 arrhythmogenic right ventricular cardiomyopathy registries in America and Europe. We classified the desmosomal variants, defined the contribution of unique versus nonunique (ie, not family-specific) P/LP variants, and identified the frequency and characteristics of de novo variants. Next, we haplotyped nonunique variants to determine how often they likely represent a single mutation event in a common ancestor (implied by shared haplotypes) versus multiple mutation events at the same genetic location.

Results: Of 501 arrhythmogenic right ventricular cardiomyopathy probands, 322 (64.3%) carried 327 desmosomal P/LP variants. Most variants (n=247, 75.6%, in 245 patients) were identified in more than one proband and, therefore, considered nonunique. For 212/327 variants (64.8%) genetic cascade screening was performed extensively enough to identify the parental origin of the P/LP variant. Only 3 variants were de novo, 2 of which were whole gene deletions. For 24 nonunique P/LP PKP2 variants, haplotyping was conducted in 183 available families. For all 24 variants, multiple seemingly unrelated families sharing identical haplotypes were identified, suggesting that these variants originate from common founders.

Conclusions: Most desmosomal P/LP variants are inherited, nonunique, and originate from ancient founders. Two of 3 de novo variants were large deletions. These observations inform genetic testing, cascade screening, and variant adjudication.
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http://dx.doi.org/10.1161/CIRCGEN.119.002467DOI Listing
August 2019

A tailored approach towards informing relatives at risk of inherited cardiac conditions: study protocol for a randomised controlled trial.

BMJ Open 2019 07 9;9(7):e025660. Epub 2019 Jul 9.

Department of Clinical Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Introduction: In current practice, probands are asked to inform relatives about the possibility of predictive DNA testing when a pathogenic variant causing an inherited cardiac condition (ICC) is identified. Previous research on the uptake of genetic counselling and predictive DNA testing in relatives suggests that not all relatives are sufficiently informed. We developed a randomised controlled trial to evaluate the effectiveness of a tailored approach in which probands decide together with the genetic counsellor which relatives they inform themselves and which relatives they prefer to have informed by the genetic counsellor. Here, we present the study protocol of this randomised controlled trial.

Methods: A multicentre randomised controlled trial with parallel-group design will be conducted in which an intervention group receiving the tailored approach will be compared with a control group receiving usual care. Adult probands diagnosed with an ICC in whom a likely pathogenic or pathogenic variant is identified will be randomly assigned to the intervention or control group (total sample: n=85 probands). Primary outcomes are uptake of genetic counselling and predictive DNA testing by relatives (total sample: n=340 relatives). Secondary outcomes are appreciation of the approach used and impact on familial and psychological functioning, which will be assessed using questionnaires. Relatives who attend genetic counselling will be asked to fill out a questionnaire as well.

Ethics And Dissemination: Ethical approval was obtained from the Medical Ethical Committee of the Amsterdam University Medical Centres (MEC 2017-145), the Netherlands. All participants will provide informed consent prior to participation in the study. Results of the study on primary and secondary outcome measures will be published in peer-reviewed journals.

Trial Registration Number: NTR6657; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615798PMC
July 2019

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
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http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019

Heritability in genetic heart disease: the role of genetic background.

Open Heart 2019;6(1):e000929. Epub 2019 May 28.

Heart Center, Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or 'modifier genes'. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.

Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.

Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.

Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.
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http://dx.doi.org/10.1136/openhrt-2018-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546190PMC
February 2021

How to inform relatives at risk of hereditary diseases? A mixed-methods systematic review on patient attitudes.

J Genet Couns 2019 10 19;28(5):1042-1058. Epub 2019 Jun 19.

Department of Clinical Genetics, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.

When a genetic disease-causing variant causing autosomal dominant diseases is identified, predictive DNA testing is possible for at-risk relatives to investigate whether they are carrying the familial variant. In current practice, the proband is asked to inform at-risk relatives, often supported by a family letter. This review summarizes the literature on preferences of probands and relatives regarding how and by whom at-risk relatives should be informed. A search involving digital databases (Pubmed, Medline, and PsycInfo) focusing on patient attitudes toward informing relatives at risk of autosomal dominant onco-, cardio-, or neurogenetic disease, resulted in 1,431 screened records, of which 117 full-text papers were assessed. Eventually, 32 studies were selected. This review shows that a majority of participants was in favor of someone in the family to inform their at-risk relatives, with participants generally feeling responsible for informing relatives at risk themselves. However, variation in patient preferences regarding who should inform was observed. Face-to-face disclosure by the proband with additional information material for relatives provided by HCPs was most appreciated. Actively offered support of healthcare professionals was desired. In conclusion, although the family-mediated approach was appreciated by a majority of participants, support by healthcare professionals was desired. By taking patient attitudes into account, the approach used to inform at-risk relatives could be improved. Subsequently, more relatives will be informed and enabled to attend genetic counseling and make an informed decision regarding predictive DNA testing. Further research on patient attitudes, specifying for disease type and cultural background, is needed.
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http://dx.doi.org/10.1002/jgc4.1143DOI Listing
October 2019

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report.

Eur J Heart Fail 2019 08 18;21(8):955-964. Epub 2019 Jun 18.

Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.
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http://dx.doi.org/10.1002/ejhf.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685753PMC
August 2019

Fetal methotrexate syndrome: A systematic review of case reports.

Reprod Toxicol 2019 08 8;87:125-139. Epub 2019 Jun 8.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the 'fetal methotrexate syndrome'. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome.
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http://dx.doi.org/10.1016/j.reprotox.2019.05.066DOI Listing
August 2019

UNRAVEL: big data analytics research data platform to improve care of patients with cardiomyopathies using routine electronic health records and standardised biobanking.

Neth Heart J 2019 Sep;27(9):426-434

Department of Cardiology, Division Heart & Lungs, University Medical Centre Utrecht, University of Utrecht, Utrecht, The Netherlands.

Introduction: Despite major advances in our understanding of genetic cardiomyopathies, they remain the leading cause of premature sudden cardiac death and end-stage heart failure in persons under the age of 60 years. Integrated research databases based on a large number of patients may provide a scaffold for future research. Using routine electronic health records and standardised biobanking, big data analysis on a larger number of patients and investigations are possible. In this article, we describe the UNRAVEL research data platform embedded in routine practice to facilitate research in genetic cardiomyopathies.

Design: Eligible participants with proven or suspected cardiac disease and their relatives are asked for permission to use their data and to draw blood for biobanking. Routinely collected clinical data are included in a research database by weekly extraction. A text-mining tool has been developed to enrich UNRAVEL with unstructured data in clinical notes.

Preliminary Results: Thus far, 828 individuals with a median age of 57 years have been included, 58% of whom are male. All data are captured in a temporal sequence amounting to a total of 18,565 electrocardiograms, 3619 echocardiograms, data from over 20,000 radiological examinations and 650,000 individual laboratory measurements.

Conclusion: Integration of routine electronic health care in a research data platform allows efficient data collection, including all investigations in chronological sequence. Trials embedded in the electronic health record are now possible, providing cost-effective ways to answer clinical questions. We explicitly welcome national and international collaboration and have provided our protocols and other materials on www.unravelrdp.nl .
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http://dx.doi.org/10.1007/s12471-019-1288-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712144PMC
September 2019