Titin-truncating variants affect heart function in disease cohorts and the general population

Schäfer, Sebastian; Marvao, Antonio de; Adami, Eleonora; Fiedler, Lorna R.; Ng, Benjamin; Khin, Ester; Rackham, Owen J. L.; Heesch, Sebastiaan van; Pua, Chee Jian; Miao, Kui; Walsh, Roddy; Tayal, Upasana; Prasad, Sanjay; Dawes, Timothy J W; Ko, Nicole S. J.; Sim, David; Chan, Laura; Chin, Calvin; Mazzarotto, Francesco; Barton, Paul J.R.; Kreuchwig, Franziska; Kleijn, Dominique P.V. de; Totman, Teresa; Biffi, Carlo; Tee, Nicole; Rueckert, Daniel; Schneider, Valentin; Faber, Allison; Regitz‐Zagrosek, Vera; Seidman, Jonathan G.; Seidman, Christine E.; Linke, Wolfgang A.; Kovalik, Jean‐Paul; O’Regan, Declan P.; Ware, James S.; Hübner, Norbert; Cook, Stuart A.

doi:10.1038/ng.3719

Cited by 252 publications

(326 citation statements)

References 75 publications

(128 reference statements)

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“…These truncating variants mainly appeared in the TTN A-band or other constitutively expressed exons, as is also reported in dilated cardiomyopathy. 21 In addition, they observed significant enrichment of TTNtv for co-occurrence with other rare candidate variants, which seems to be in alignment with accumulating data that a secondary factor (genetic or environmental) is often required for a clinical phenotype to manifest with TTNtv variants. To our knowledge, this is the first study demonstrating the association of TTNtv variants with LVNC, establishing the importance of this gene in LVNC.…”

Section: Titin and Lvncsupporting

confidence: 66%

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Rhee

Grove

Ashley

2017

Circ Cardiovasc Genet

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Section: Titin and Lvncsupporting

confidence: 66%

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Rhee

Grove

Ashley

2017

Circ Cardiovasc Genet

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“…Mutations in TTN have pleiotropic effects and have been associated with tibial muscular dystrophy, 21 hypertrophic cardiomyopathy, 22,26 and dilated cardiomyopathy. 20,23–25 One-third of patients develop heart failure within five years of AF diagnosis in community-based settings, and AF is common after the onset of heart failure. 33 The co-occurrence of TTN LOF variation in both AF and dilated cardiomyopathy suggests that impaired sarcomere structure or function may be an overlapping pathophysiologic mechanism in at least some cases.…”

Section: Discussionmentioning

confidence: 99%

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Choi¹,

Weng²,

Roselli³

et al. 2018

JAMA

148

125

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Importance Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective To perform large-scale, deep-coverage whole genome sequencing to identify genetic variants related to AF. Design, Setting, Participants The National Heart Lung and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high depth, whole genome sequencing between 2014 and 2017 in 18,526 individuals from the U.S., Mexico, Puerto-Rico, Costa-Rica, Barbados, and Samoa. This case-control study included 2,781 patients with early onset AF from 9 studies and identified 4,959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank and the MyCode Study consisting of 346,546 and 42,782 participants, respectively. Exposures Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures Early-onset AF defined as AF onset < 66 years of age. Due to multiple testing, the significance threshold for the rare variant analysis was P=4.55 X 10−3. Results Among 2,781 early-onset AF cases, 72.1% were male, and the mean age of AF onset was 48.7±10.2 years. Samples underwent whole genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least one LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of cases compared with 1.1% in controls. The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend 4.92×10−4) and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (odds ratio = 5.94; 95% CI, 2.64–13.35; P=1.65×10−5). The association between TTN LOF variants and AF was replicated in an independent 1,582 early-onset AF cases and 41,200 controls (odds ratio = 2.16; 95% CI, 1.19–3.92; P=0.01). Conclusions and Relevance In a case control study, there was a statistically significant association between a LOF variant in the gene TTN and early-onset AF, with the variant present in a small percentage of cases. Further research is required to understand whether this is a causal relationship.

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“…There is a tendency for TTN truncations in DCM to distribute to the A band, rather than the I band 66 , and TTN truncations can also be associated with mild DCM 70 . A recent study showed that truncating variants in the general population are linked to eccentric cardiac remodeling, suggesting that TTN truncations may be “at-risk” alleles 71 .…”

Section: Dcm Geneticsmentioning

confidence: 99%

“…A mouse models with an in frame deletion in the PEVK region of TTN develops diastolic dysfunction, consistent with the complex role of titin for both systolic and diastolic dysfunction 82 . In both rats and mice with heterozygous TTN truncation mutations, additional stressors like transaortic constriction are used to promote the development of DCM 71, 83 .…”

Section: Dcm Geneticsmentioning

confidence: 99%

Dilated Cardiomyopathy

2017

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Nonischemic dilated cardiomyopathy often has a genetic etiology. Because of the large number of genes and alleles attributed to dilated cardiomyopathy, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at-risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of dilated cardiomyopathy, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to dilated cardiomyopathy and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of dilated cardiomyopathy, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

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Titin-truncating variants affect heart function in disease cohorts and the general population

Cited by 252 publications

References 75 publications

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

Dilated Cardiomyopathy

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