Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype–Phenotype Correlation and Consequences in Genetic Counseling

Clinical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis probands have been evaluated in several large cohorts. However, few data available on intrafamilial expressivity. To evaluate phenotypical variability, we selected family members carrying a unique TTN variant recorded cardiac information. cohort included 332 (314 TTNtv 18 with silico predicted in-frame exon skipping probands) 191 relatives including 98 affected members. Within families, 96% presented same cardiomyopathy subtype as proband, 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, reported that carry variants; they DCM (84%) patients but lower rate rhythm disorders (0% vs. 29% respectively). In this work, extend spectrum associated show within family, is homogenous expressivity could vary. Such results helpful for appropriate counseling to better predict manage mutation carriers.

Язык: Английский

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Genotype-phenotype insights of pediatric dilated cardiomyopathy

Frontiers in Pediatrics, Год журнала: 2025, Номер 13

Опубликована: Янв. 31, 2025

Dilated cardiomyopathy (DCM) in children is a severe myocardial disease characterized by enlargement of the left ventricle or both ventricles with impaired contractile function. DCM can cause adverse consequences such as heart failure, sudden death, thromboembolism, and arrhythmias. This article reviews latest advances genotype phenotype research pediatric DCM. With development gene sequencing technologies, considerable progress has been made genetic on Research shown that exhibits notable heterogeneity, over 100 DCM-related genes identified to date, primarily involving functions calcium handling, cytoskeleton, ion channels. As human genomic variations are linked phenotypes, phenotypes influenced numerous across entire genome. Children display high heterogeneity early onset, rapid progression, poor prognosis. The architecture markedly differs from adult DCM, necessitating analyses through clinical phenotyping, familial cosegregation studies, functional validation. Clarifying genotype-phenotype relationship improve diagnostic accuracy, enhance prognosis, guide follow-up treatment for genotype-positive phenotype-negative patients testing, providing new insights precision medicine. Future should further explore novel pathogenic mutations strengthen correlation facilitate precise diagnosis children.

Язык: Английский

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TTN:c.12478del in proximal I-band of titin represents a common molecular cause of dilated cardiomyopathy in Slovenian patients

Orphanet Journal of Rare Diseases, Год журнала: 2025, Номер 20(1)

Опубликована: Фев. 28, 2025

Abstract Background Titin truncating variants ( TTN tv-s) are the most common genetic cause of dilated cardiomyopathy (DCM). Only rare tv-s in constitutively expressed exons A-band protein titin associated with DCM according to guidelines, however, studies large cohorts patients suggest that region where is wider, extending at least into I-band. The aim this study was describe molecular pathology Slovenian and clinically characterise recurrent tv. Results We collected all identified using next-generation sequencing testing between 2010 July 2024, resulting 42 unique 54 patients. :c.12478del variant, affecting not but proximal I-band, specifically cardiac-specific N2Bus region, found be present seven (11.6%) probands DCM. Genetic characterisation revealed a probable founder origin variant. Clinical these phenotype consistent severely reduced left ventricular ejection fraction probands. Three (43%) had atrial fibrillation and/or non-sustained tachycardia. Based on literature reports evidence supporting pathogenicity variant we classified I-band as (likely) pathogenic. Therefore, 33 (78.6%) were pathogenic (13 19 20 25 probands), meaning 44 genotype-positive DCM, explaining 73.3% Conclusion report an almost threefold higher diagnostic yield compared previously reported findings from other populations. also highlight need for screening geographical region.

Язык: Английский

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Prevalence of deleterious cardiomyopathy variants in early-onset atrial fibrillation

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure, and death. Recent studies suggests that individuals early onset AF could be at developing failure dilated cardiomyopathy. This study aimed to identifying genetic variants in broad panel cardiomyopathy genes among early-onset individuals. We conducted targeted sequencing 29 cardiomyopathy-associated 478 below 45 years age from Danish cohort. Additionally, we analyzed whole exome data 374,289 the UK Biobank, including 29,108 AF. The cohort was stratified by diagnosis, pre-existing were excluded. focused on rare, truncating predicted lead loss function, potentially deleterious missense Biobank. In cohort, 42 (8.8%) had known genes. Biobank analysis showed inverse dose-response-like relationship between prevalence variants, ranging 3.8% <45 group 1.4% without diagnosis. rare similar pattern. identified high supports recent guideline suggestions indicates testing surveillance for relevant selected

Язык: Английский

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Development of an alkaliptosis-related lncRNA risk model and immunotherapy target analysis in lung adenocarcinoma

Frontiers in Genetics, Год журнала: 2025, Номер 16

Опубликована: Апрель 8, 2025

Lung cancer has the highest mortality rate among all cancers worldwide. Alkaliptosis is characterized by a pH-dependent form of regulated cell death. In this study, we constructed model related to alkaliptosis-associated long non-coding RNAs (lncRNAs) and developed prognosis-related framework, followed identification potential therapeutic drugs. The TCGA database was utilized obtain RNA-seq-based transcriptome profiling data, clinical information, mutation data. We conducted multivariate Cox regression analysis identify alkaliptosis-related lncRNAs. Subsequently, employed training group construct prognostic testing validate model's accuracy. Calibration curves were generated illustrate discrepancies between predicted observed outcomes. Principal Component Analysis (PCA) performed investigate distribution LUAD patients across high- low-risk groups. Additionally, Gene Ontology (GO) Set Enrichment (GSEA) conducted. Immune infiltration Tumor Mutational Burden (TMB) analyses carried out using CIBERSORT maftools algorithms. Finally, "oncoPredict" package predict immunotherapy sensitivity further forecast anti-tumor immune qPCR used for experimental verification. identified 155 lncRNAs determined that 5 these serve as independent factors. progression-free survival (PFS) overall (OS) rates significantly higher than those high-risk group. risk signature functions factor other variables. Different stages (I-II III-IV) effectively lung adenocarcinoma (LUAD) patients, can reliably signatures. GSEA revealed processes chromosome segregation response activation enriched in both exhibited lower fraction plasma cells proportion activated CD4 memory T cells. OS low TMB compared high Furthermore, drug greater These may biomarkers treating patients. summary, construction an lncRNA provides new insights into diagnosis treatment advanced

Язык: Английский

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Fentanyl and Sudden Death—A Postmortem Perspective for Diagnosing and Predicting Risk

Diagnostics, Год журнала: 2024, Номер 14(17), С. 1995 - 1995

Опубликована: Сен. 9, 2024

Sudden, unexpected deaths are extremely difficult for families, especially when the victim is a child. Most sudden occur due to cardiovascular issues, and smaller number (approximately one-quarter) attributed other causes, such as epilepsy. The medicinal non-medicinal use of synthetic opioid fentanyl, which can cause breathing problems, frequently involved in these deaths. It also being found more often autopsies death cases, overdose from illicit drugs containing fentanyl increasing. There cases it mixed with drugs. A gene known KCNH2 or human ether-a-go-go-related (hERG), heart’s electrical activity, be related abnormal heart rhythms. This gene, along others, may play role use. In response, we have examined scientific literature on genetic variations that death, impact this process, potential benefits testing victims offer counseling their family members.

Язык: Английский

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Investigating Inherited Heart Diseases Using Human Induced Pluripotent Stem Cell-Based Models

Life, Год журнала: 2024, Номер 14(11), С. 1370 - 1370

Опубликована: Окт. 25, 2024

Inherited heart diseases (IHDs) are caused by genetic mutations that disrupt the physiological structure and function of heart. Understanding mechanisms behind these is crucial for developing personalised interventions in cardiovascular medicine. Development induced pluripotent stem cells, which can then be differentiated to any nucleated adult cell type, has enabled creation single-cell multicellular models, providing unprecedented insights into pathophysiology IHDs. This review provides a comprehensive overview recent advancements human iPSC models used dissect molecular underpinnings common We examine tissue engineering approaches, such as cardiac organoids, engineered tissue, co-culture systems, simulate complex intercellular interactions within tissue. Recent offer more physiologically relevant platform study disease mechanisms, enabling researchers observe cellular interactions, progression, identify therapeutic strategies. By leveraging innovative we gain deeper underlying IHDs, ultimately paving way effective diagnostic

Язык: Английский

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Ehlers–Danlos Syndrome Association with Nondilated Cardiomyopathy

Research in Cardiovascular Medicine, Год журнала: 2024, Номер 13(4), С. 141 - 143

Опубликована: Окт. 1, 2024

Abstract Ehlers–Danlos syndrome (EDS), a genetically inherited collagen defect, results in altered function of different organs such as joint hyper-mobility and skin laxity. It also affects the cardiovascular, immune, autonomic nerves, gastrointestinal systems. This paper presents report patient with increased flexibility palpitations. Clinical evaluation revealed diagnosis EDS nondilated cardiomyopathy.

Язык: Английский

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TTN Variants, Dilated Cardiomyopathy, and Arrhythmic Causes by Autopsy Among Countywide Sudden Deaths

JACC. Clinical electrophysiology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

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