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Article: High-Sensitivity Cardiac Troponin T to Exclude Cardiac Involvement in TTR Variant Carriers and ATTRv Amyloidosis Patients.

Tingen, Hendrea S A / Berends, Milou / Tubben, Alwin / Bijzet, Johan / Houwerzijl, Ewout J / Muntinghe, Friso L H / Kroesen, Bart-Jan / van der Zwaag, Paul A / van der Meer, Peter / Slart, Riemer H J A / Hazenberg, Bouke P C / Nienhuis, Hans L A

Journal of clinical medicine

2024 Volume 13, Issue 3

Abstract: 1) Background: Individuals carrying a pathogenic transthyretin gene variant ( ...

Abstract	(1) Background: Individuals carrying a pathogenic transthyretin gene variant (
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm13030810
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Article ; Online: Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis.

Berends, Milou / Brunger, Anne F / Bijzet, Johan / Kroesen, Bart-Jan / Drost, Gea / Lange, Fiete / Teunissen, Charlotte E / In 't Veld, Sjors / Vrancken, Alexander Fje / Gans, Reinold O B / Hazenberg, Bouke P C / van der Zwaag, Paul A / Nienhuis, Hans L A

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis

2024 , Page(s) 1–10

Abstract: Objective: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and : Methods: sNfL levels were assessed longitudinally in ... ...

Abstract	Objective: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and Methods: sNfL levels were assessed longitudinally in persistently asymptomatic Results: sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic Conclusion: sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1205246-2
ISSN	1744-2818 ; 1350-6129
ISSN (online)	1744-2818
ISSN	1350-6129
DOI	10.1080/13506129.2024.2327342
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Article ; Online: Phenotypic variability of filamin C-related cardiomyopathy: Insights from a novel Dutch founder variant.

Schoonvelde, Stephan A C / Ruijmbeek, Claudine W B / Hirsch, Alexander / van Slegtenhorst, Marjon A / Wessels, Marja W / von der Thüsen, Jan H / Baas, Annette F / Stroeks, Sophie L V M / Verdonschot, Job A J / van der Zwaag, Paul A / Verhagen, Judith M A / Michels, Michelle

Heart rhythm

2023 Volume 20, Issue 11, Page(s) 1512–1521

Abstract: Background: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM.: Objectives: The ... ...

Abstract	Background: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM. Objectives: The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant. Methods: Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined. Results: Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19-67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (<45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribution. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275 and 650 years ago. Conclusion: The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs∗23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function.
MeSH term(s)	Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Biological Variation, Population ; Cardiomyopathies/genetics ; Cardiomyopathy, Dilated/genetics ; Contrast Media ; Filamins/genetics ; Gadolinium ; Retrospective Studies
Chemical Substances	Contrast Media ; Filamins ; Gadolinium (AU0V1LM3JT) ; FLNC protein, human
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2229357-7
ISSN	1556-3871 ; 1547-5271
ISSN (online)	1556-3871
ISSN	1547-5271
DOI	10.1016/j.hrthm.2023.08.003
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Article ; Online: Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers.

Lopera-Maya, Esteban A / Li, Shuang / de Brouwer, Remco / Nolte, Ilja M / van Breen, Justin / Jongbloed, Jan D H / Swertz, Morris A / Snieder, Harold / Franke, Lude / Wijmenga, Cisca / de Boer, Rudolf A / Deelen, Patrick / van der Zwaag, Paul A / Sanna, Serena

Journal of cardiovascular translational research

2023 Volume 16, Issue 6, Page(s) 1251–1266

Abstract: The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at ... ...

Abstract	The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (- 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (r
MeSH term(s)	Humans ; Aged ; Mutation ; Cardiomyopathies/diagnosis ; Cardiomyopathies/genetics ; Calcium-Binding Proteins/genetics ; Genotype
Chemical Substances	phospholamban ; Calcium-Binding Proteins
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2422411-X
ISSN	1937-5395 ; 1937-5387
ISSN (online)	1937-5395
ISSN	1937-5387
DOI	10.1007/s12265-022-10347-5
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Article: Validation of New Gene Variant Classification Methods: a Field-Test in Diagnostic Cardiogenetics.

Alimohamed, Mohamed Z / Westers, Helga / Vos, Yvonne J / Van der Velde, K Joeri / Sijmons, Rolf H / Van der Zwaag, Paul A / Sikkema-Raddatz, Birgit / Jongbloed, Jan D H

Frontiers in genetics

2022 Volume 13, Page(s) 824510

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2022-03-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2022.824510
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Article ; Online: SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics.

Alimohamed, Mohamed Z / Boven, Ludolf G / van Dijk, Krista K / Vos, Yvonne J / Hoedemaekers, Yvonne M / van der Zwaag, Paul A / Sijmons, Rolf H / Jongbloed, Jan D H / Sikkema-Raddatz, Birgit / Westers, Helga

Gene

2022 Volume 851, Page(s) 146984

Abstract: Background: Splice prediction algorithms currently used in routine DNA diagnostics have limited sensitivity and specificity, therefore many potential splice variants are classified as variants of uncertain significance (VUSs). However, functional ... ...

Abstract	Background: Splice prediction algorithms currently used in routine DNA diagnostics have limited sensitivity and specificity, therefore many potential splice variants are classified as variants of uncertain significance (VUSs). However, functional assessment of VUSs to test splicing is labour-intensive and time-consuming. We developed a decision tree to prioritise potential splice variants for functional studies and functionally verified the outcome of the decision tree. Materials and methods: We built the decision tree, SEPT-GD, by setting thresholds for the splice prediction programs implemented in Alamut. A set of 343 variants with known effects on splicing was used as control for sensitivity and specificity. We tested SEPT-GD using variants from a Dutch cardiomyopathy cohort of 2002 patients that were previously classified as VUS and predicted to have a splice effect according to diagnostic rules. We then selected 12 VUSs ranked by SEPT-GD to functionally verify the predicted effect on splicing using a minigene assay: 10 variants predicted to have a strong effect and 2 with a weak effect. RT-PCR was performed for nine variants. Variant classification was re-evaluated based on the functional test outcome. Results: Compared to similar individually tested algorithms, SEPT-GD shows higher sensitivity (91 %) and comparable specificity (88 %) for both consensus (dinucleotides at the start and end of the intron, GT at the 5' end and AG at the 3' end) and non-consensus splice-site variants (excluding middle of exon variants). Using clinical diagnostic criteria, 1295 unique variants in our cardiomyopathy cohort had originally been classified as VUSs, with 57 predicted by Alamut to have an effect on splicing. Using SEPT-GD, we prioritised 31 variants in 40 patients. In the minigene assay, all 12 variants showed results concordant with SEPT-GD predictions. RT-PCR confirmed the minigene results for two variants, TMEM43 c.1000 + 5G > T and TTN c.25922-6 T > G. Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were reclassified as likely pathogenic. Conclusion: SEPT-GD outperforms the tools commonly used for RNA splicing prediction and improves prioritisation of variants in cardiomyopathy genes for functional splicing analysis in a diagnostic setting.
MeSH term(s)	Humans ; RNA Splice Sites/genetics ; Decision Trees ; Genetic Variation ; RNA Splicing ; Cardiomyopathies/diagnosis ; Cardiomyopathies/genetics
Chemical Substances	RNA Splice Sites
Language	English
Publishing date	2022-10-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2022.146984
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Zs.A 1357: Show issues

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Article ; Online: Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

van der Heide, Myrthe Y C / Verstraelen, Tom E / van Lint, Freyja H M / Bosman, Laurens P / de Brouwer, Remco / Proost, Virginnio M / van Drie, Esmée / Taha, Karim / Zwinderman, Aeilko H / Dickhoff, Cathelijne / Schoonderwoerd, Bas A / Germans, Tjeerd / Houweling, Arjan C / Gimeno-Blanes, Juan R / van der Zwaag, Paul A / de Boer, Rudolf A / Cox, Moniek G P J / van Tintelen, J Peter / Wilde, Arthur A M

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

2024 Volume 26, Issue 4

Abstract: Aims: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention ... ...

Abstract	Aims: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. Methods and results: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. Conclusion: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.
MeSH term(s)	Female ; Humans ; Male ; Arrhythmias, Cardiac/diagnosis ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/therapy ; Calcium-Binding Proteins/genetics ; Death, Sudden, Cardiac/etiology ; Death, Sudden, Cardiac/prevention & control ; Defibrillators, Implantable ; Reproducibility of Results ; Risk Factors ; Adult ; Middle Aged
Chemical Substances	Calcium-Binding Proteins ; phospholamban
Language	English
Publishing date	2024-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1449879-0
ISSN	1532-2092 ; 1099-5129
ISSN (online)	1532-2092
ISSN	1099-5129
DOI	10.1093/europace/euae069
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Article ; Online: Coexistence of wild type and hereditary ATTR amyloidosis in one family.

Feenstra, Josine G / Nienhuis, Hans L A / Bijzet, Johan / van der Zwaag, Paul A / van den Berg, Maarten P / Hazenberg, Bouke P C

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis

2019 Volume 27, Issue 1, Page(s) 71–72

MeSH term(s)	Aged, 80 and over ; Amyloid Neuropathies, Familial/genetics ; Female ; Humans ; Male ; Pedigree
Language	English
Publishing date	2019-11-13
Publishing country	England
Document type	Case Reports ; Letter ; Video-Audio Media
ZDB-ID	1205246-2
ISSN	1744-2818 ; 1350-6129
ISSN (online)	1744-2818
ISSN	1350-6129
DOI	10.1080/13506129.2019.1690444
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Article ; Online: ECG-only explainable deep learning algorithm predicts the risk for malignant ventricular arrhythmia in phospholamban cardiomyopathy.

van de Leur, Rutger R / de Brouwer, Remco / Bleijendaal, Hidde / Verstraelen, Tom E / Mahmoud, Belend / Perez-Matos, Ana / Dickhoff, Cathelijne / Schoonderwoerd, Bas A / Germans, Tjeerd / Houweling, Arjan / van der Zwaag, Paul A / Cox, Moniek G P J / Peter van Tintelen, J / Te Riele, Anneline S J M / van den Berg, Maarten P / Wilde, Arthur A M / Doevendans, Pieter A / de Boer, Rudolf A / van Es, René

Heart rhythm

2024

Abstract: Background: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a ...

Abstract	Background: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model. Objective: This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data. Methods: A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression. Results: The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai). Conclusion: Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up.
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2229357-7
ISSN	1556-3871 ; 1547-5271
ISSN (online)	1556-3871
ISSN	1547-5271
DOI	10.1016/j.hrthm.2024.02.038
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Article: Exercise does not influence development of phenotype in PLN p.(Arg14del) cardiomyopathy.

van Lint, Freyja H M / Hassanzada, Fahima / Verstraelen, Tom E / Wang, Weijia / Bosman, Laurens P / van der Zwaag, Paul A / Oomen, Toon / Calkins, Hugh / Murray, Brittney / Tichnell, Crystal / Beuren, Thais M A / Asselbergs, Folkert W / Houweling, Arjan / van den Berg, Maarten P / Wilde, Arthur A M / James, Cynthia A / van Tintelen, J Peter

Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation

2023 Volume 31, Issue 7-8, Page(s) 291–299

Abstract: Background: Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.( ... ...

Abstract	Background: Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.(Arg14del) variant in the PLN gene are frequently diagnosed with ARVC or dilated cardiomyopathy (DCM). The aim of this study was to evaluate the effect of exercise in PLN p.(Arg14del) carriers. Methods: In total, 207 adult PLN p.(Arg14del) carriers (39.1% male; mean age 53 ± 15 years) were interviewed on their regular physical activity since the age of 10 years. The association of exercise with diagnosis of ARVC, DCM, sustained VA and hospitalisation for heart failure (HF) was studied. Results: Individuals participated in regular physical activities with a median of 1661 metabolic equivalent of task (MET) hours per year (31.9 MET-hours per week) until clinical presentation. The 50% most and least active individuals had a similar frequency of sustained VA (18.3% vs 18.4%; p = 0.974) and hospitalisation for HF (9.6% vs 8.7%; p = 0.827). There was no relationship between exercise and survival free from (incident) sustained VA (p = 0.65), hospitalisation for HF (p = 0.81), diagnosis of ARVC (p = 0.67) or DCM (p = 0.39) during follow-up. In multivariate analyses, exercise was not associated with sustained VA or HF hospitalisation during follow-up in this relatively not-active cohort. Conclusion: There was no association between the amount of exercise and the susceptibility to develop ARVC, DCM, VA or HF in PLN p.(Arg14del) carriers. This suggested unaffected PLN p.(Arg14del) carriers can safely perform mild-moderate exercise, in contrast to desmosomal variant carriers and ARVC patients.
Language	English
Publishing date	2023-07-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2211468-3
ISSN	1876-6250 ; 1568-5888 ; 0929-7456
ISSN (online)	1876-6250
ISSN	1568-5888 ; 0929-7456
DOI	10.1007/s12471-023-01800-4
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