A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3)

Pantou, Malena P.; Gourzi, Polyxeni; Gkouziouta, Aggeliki; Armenis, Iakovos; Kaklamanis, Loukas; Zygouri, Christianna; Constantoulakis, Pantelis; Adamopoulos, Stamatis; Degiannis, Dimitrios

doi:10.1186/s12881-019-0793-z

Cited by 13 publications

(11 citation statements)

References 23 publications

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“…In 2018 Streff et al [ 32 ] reported a complex phenotype, characterized by the co-occurrence of early onset DCM together with Amish nemaline myopathy, in a child carrying a homozygous contiguous gene deletion of about 11 kb, which encompassed the last exon of TNNI3 . Another biallelic variant, although in relation to a remarkably different cardiac phenotype, was published in 2019, when Pantou et al [ 33 ] identified a homozygous p.(Asp196His) substitution in three adult siblings, two of them suffering from late onset RCM and one from HCM, while heterozygous carriers in the family were apparently healthy. Kühnisch et al [ 28 ] further widened the phenotypic and genotypic spectrum by identifying two unrelated pediatric patients, one with early onset DCM and the other with a familial form of LVNC, carrying homozygous p.Arg69Alafs* and c.24+2T>A p.(?)…”

Section: Discussionmentioning

confidence: 99%

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

Sorrentino

Gabbiato

Canciani

et al. 2023

Genes

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The TNNI3 gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous TNNI3 missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of TNNI3 null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy. Here, we expand the case series reporting two unrelated patients afflicted with early onset dilated cardiomyopathy, due to homozygosity for the p.Arg98* TNNI3 variant, which had thus far been documented only in heterozygous patients and apparently healthy carriers, and the recurrent p.Arg69Alafs*8 variant, respectively. A review of previously reported biallelic TNNI3 loss-of-function variants and their associated cardiac phenotypes was also performed.

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Section: Discussionmentioning

confidence: 99%

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

Sorrentino

Gabbiato

Canciani

et al. 2023

Genes

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“…Several gene mutations have been recognized as a cause of RCM and TNNI3 seems to be the most prevalent disease gene in RCM ( Figure 3 ). 2 , 3 , 5 , 8 , 11–14 …”

Section: Discussionmentioning

confidence: 99%

“…endomyocardial fibrosis) forms. 2 , 3 Mutations in sarcomeric and cytoskeletal genes, amongst them the troponin complex subunits T ( TNNT2 Troponin T) 4 and I ( TNNI3 Troponin I), 5 have been associated with hereditary RCM.…”

Section: Introductionmentioning

confidence: 99%

A novel Troponin I mutation associated with severe restrictive cardiomyopathy—a case report of a 27-year-old woman with fatigue

Gerhardt

Monserrat

Landmesser

et al. 2022

European Heart Journal - Case Reports

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Background Restrictive cardiomyopathy is rare and heterogeneous in origin, clinical manifestation and prognosis. Familial forms have, amongst others, been associated with mutations in the TNNI3 gene. We present a case of familial restrictive cardiomyopathy associated with a novel TNNI3 mutation including longitudinal Follow-up. Case summary A 27-year-old woman was evaluated for fatigue in the context of a family history of sudden cardiac death. Echocardiography was normal except for mild left atrial dilatation. Focused genetic screening, limited to the most common genes associated with cardiomyopathy, was unremarkable in 2006. In biopsy, mild inflammatory cardiomyopathy was diagnosed and the patient was discharged. 13 years later, rapid clinical deterioration occurred in the context of new-onset atrial fibrillation. Echocardiography now showed gross bi-atrial dilatation and evidence of diastolic dysfunction. Based on haemodynamic tracings during angiography, a diagnosis of restrictive cardiomyopathy was made. In 2018, next-generation-sequencing revealed the hitherto undescribed Troponin I variant Lys193Glu in a functionally critical domain. Hemodynamic stabilisation was achieved by pulmonary vein isolation. Until now, the patient remains symptom-free under diuretic treatment. Discussion Diagnosis of restrictive cardiomyopathy is complicated by often oligosymptomatic early presentation and a diverse clinical picture. Thorough medical and family history and early invasive hemodynamic tracing is indispensable in diagnosis. Therapy-refractory atrial fibrillation should raise suspicion. Reporting of longitudinal Follow-up cases is essential to better understand early symptoms, development and prognosis of this rare disease. Broad genetic testing in unclear cases has become more available and affordable and should be considered early in the diagnostic workflow.

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“…Cardiac troponin I is highly specific for heart muscle and higher concentrations in the blood are associated with higher general in-hospital mortality for a number of illnesses (25). It serves as a sensor of intracellular calcium, regulating the interaction between thick and thin sarcomere filaments during the heart muscle contraction (26). We hypothesise that this protein may be relevant to COVID-19 as ∼40% of deaths in a cohort from Wuhan (27) were attributed to myocardial damage and heart failure, as well as increased mortality in individuals with both COVID-19 and acute cardiac injury (28).…”

Section: Discussionmentioning

confidence: 99%

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Palmos

Millischer

Menon

et al. 2021

Preprint

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The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

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A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3)

Cited by 13 publications

References 23 publications

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature

A novel Troponin I mutation associated with severe restrictive cardiomyopathy—a case report of a 27-year-old woman with fatigue

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

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