Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy

Jansweijer, Joeri A.; Nieuwhof, Karin; Russo, Francesco; Hoorntje, Edgar T; Jongbloed, Jan D. H.; Deprez, Ronald H. Lekanne; Postma, Alex V.; Bronk, Marieke; Rijsingen, I. A. W. Van; Haij, Simone de; Biagini, Elena; Haelst, Paul L. van; Wijngaarden, Jan van; Berg, Maarten P. van den; Wilde, Arthur A.M.; Mannens, Marcel M.A.M.; Boer, Rudolf A. de; Spaendonck‐Zwarts, Karin Y. van; Tintelen, J. Peter van; Pinto, Yigal M.

doi:10.1002/ejhf.673

Cited by 141 publications

(129 citation statements)

References 33 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…In the study by Akinrinade et al disease penetrance increased from 53.8% at age 50 to 84.6% at age 60 and 100% at age 70 [3]. In the study by Jansweijer et al, the penetrance of DCM in TTN relatives was 29% at the age of 50 (n = 49), had increased to 58% at the age of 60 (n = 43), and further to 83% at the age of 70 (n = 36) [18]. The varied and incomplete penetrance suggests a potential role of other genetic/environmental factors in the disease onset in DCM related titinopathy.…”

Section: Discussionmentioning

confidence: 99%

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

et al. 2017

View full text Add to dashboard Cite

TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

show abstract

Section: Discussionmentioning

confidence: 99%

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

et al. 2017

View full text Add to dashboard Cite

show abstract

“…13 Data of these LMNA mutation carriers have been analyzed and used in previous studies. 6,13,14 An event was defined as a composite of the following end points: appropriate ICD therapy, out-of-hospital cardiac arrest, heart transplant (HTx)/ left ventricular assist device implantation, or death. Appropriate ICD therapy was defined as antitachycardia pacing or an ICD discharge for termination of ventricular tachycardia or fibrillation.…”

Section: Time-to-event Analysismentioning

confidence: 99%

Lamin A/C -Related Cardiac Disease

Hoorntje¹,

Bollen²,

Barge-Schaapveld³

et al. 2017

Circ Cardiovasc Genet

Self Cite

View full text Add to dashboard Cite

T he LMNA gene encodes for the intermediate filament proteins lamin A and C. LMNA mutations are associated with a wide spectrum of phenotypes ranging from progeroid syndromes, muscular disease, and lipodystrophy to isolated cardiac disease (dilated cardiomyopathy [DCM] and conduction disorders) and phenotypes consisting of combinations of these different features.1 Although their precise role is unknown, LMNA proteins are believed to play an important role in the structural integrity of the cell nucleus and in gene regulation. 2LMNA is one of the genes most frequently involved in genotyped DCM.3 Sinus node dysfunction, atrioventricular conduction disorders, and supraventricular and ventricular arrhythmias often precede or accompany DCM.4 LMNArelated cardiac disease is associated with a high incidence of major cardiac events like sudden cardiac death, appropriate implantable cardioverter-defibrillator (ICD) therapy, or endstage heart failure. DCM patients with an LMNA mutation are, in general, believed to have a poor prognosis compared with non-LMNA mutation DCM patients. 5,6 Currently, with all the new DNA-sequencing technologies implemented in routine patient care, increasing numbers Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membranepermeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p. (Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations b...

show abstract

“…DCM is a known part of the spectrum of SCN5A disease [8], but very limited data on the degree of reversibility exist [9]. Recent data show that TTN -associated DCM is more amenable to heart failure therapy than LMNA -associated DCM, suggesting that information about underlying causal genetic variants carries prognostic information [10]. …”

Section: Discussionmentioning

confidence: 99%

A Novel <b><i>SCN5A</i></b> Variant Associated with Abnormal Repolarization, Atrial Fibrillation, and Reversible Cardiomyopathy

et al. 2018

View full text Add to dashboard Cite

A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodium channel encoded by the SCN5A gene. In this study, we report a novel loss-of-function SCN5A variant, p.Ile1343Val (c.4027A>G), identified in a 42-year-old proband who presented with an unusual ECG with abnormal repolarization with biphasic T-waves in anteroseptal leads, persistent atrial fibrillation (AF), intermittent left bundle branch block (LBBB), and reversible cardiomyopathy. The patient did not meet the diagnostic criteria for Brugada syndrome, long QT syndrome, or any other known SCN5A-associated phenotype. Characterization of the biophysical properties of the variant by in vitro patch clamp experiments revealed a reduced Na⁺ current with no effect on the inactivation kinetics of the channel. This loss-of-function of Na⁺ current could explain the intermittent LBBB as well as the AF. In conclusion, we describe a unique combination of electrical and structural abnormalities associated with a novel SCN5A variant. Our findings broaden the spectrum of cardiac phenotypes associated with SCN5A channelopathy, underlining the complex clinical manifestations of genetic variations within this gene.

show abstract

Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy

Abstract: This study shows that tTTN-associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation-induced DCM or iDCM.

Cited by 141 publications

References 33 publications

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

Lamin A/C -Related Cardiac Disease

A Novel <b><i>SCN5A</i></b> Variant Associated with Abnormal Repolarization, Atrial Fibrillation, and Reversible Cardiomyopathy

Contact Info

Product

Resources

About