Titin truncating mutations: A rare cause of dilated cardiomyopathy in the young

Fatkin, Diane; Lam, Lien; Herman, Daniel S.; Benson, Craig C.; Felkin, Leanne E.; Barton, Paul J.R.; Walsh, Roddy; Candan, Şükrü; Ware, James S.; Roberts, Angharad; Chung, Wendy K.; Smoot, Leslie; Bornaun, Helen; Keogh, Anne; Macdonald, P.; Hayward, Christopher; Seidman, Jonathan G.; Roberts, Amy; Cook, Stuart A.; Seidman, Christine E.

doi:10.1016/j.ppedcard.2016.01.003

Cited by 23 publications

(22 citation statements)

References 16 publications

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“…31,38–40 Whether broader genomic analyses may uncover additional genetic contributors to CCM is worthy of study. TTNtvs are significantly prominent in DCM, occurring in 15% of ambulatory and 25% of end-stage patients, 30,31,34,38 but are rarely identified in childhood-onset DCM, 41 whereas here we identified TTNtvs in 8.1% of adults and 5.0% of children with CCM. TTNtvs found in patients with CCM, like those in patients with DCM, disrupted exons that are constitutively expressed in the heart and are overrepresented in the A-band (Table 3).…”

Section: Discussioncontrasting

confidence: 38%

Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

et al. 2019

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Section: Discussioncontrasting

confidence: 38%

Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

et al. 2019

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“…This suggests a link of TTN truncation with pediatric RCM, potentially in combination with a more complex genetic alteration, and a critical importance of both TTN alleles for postnatal development . In line with our observations, other studies showed that in children with DCM, the frequency of truncating TTN variants is much lower compared to adults …”

Section: Discussioncontrasting

confidence: 48%

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

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“…The association between DCM and TTNtv has subsequently been widely replicated [27][28][29][30][31][32][33][34] {very recent addition: TAYAL et al, JACC 18:2264-2274 (2017)}, with TTNtv accounting for ~15% of DCM cases in the largest series of unselected patients 30,33 (although much more rarely identified in paediatric cardiomyopathy 28,35 ). TTN sequencing has become adopted routinely in diagnostic laboratories, markedly increasing the yield and, therefore, utility of genetic testing in DCM for confirmatory and familial screening.…”

Section: [H1] Titin In Heart Diseasementioning

confidence: 96%

Role of titin in cardiomyopathy: from DNA variants to patient stratification

2017

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Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN). Such variation is common in the general population (up to 1% of individuals), and we consider key features that discriminate variants with disease-causing potential from those that are benign. We summarize strategies for clinical interpretation of genetic variants for use in the diagnosis of patients and the evaluation of their relatives. Finally, we consider the contemporary and potential future role for genetic stratification in cardiomyopathy and in the general population, evaluating titin variation as a predictor of outcome and treatment response for precision medicine.

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Titin truncating mutations: A rare cause of dilated cardiomyopathy in the young

Cited by 23 publications

References 16 publications

Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

Role of titin in cardiomyopathy: from DNA variants to patient stratification

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