Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant

Lamounier, Arsonval; González, Alba; Vilela, Alejandro Rodríguez; Repáraz-Andrade, Alfredo; Alcaide, Álvaro Rubio; Sousa, Ana Berta; López, C. Castañón; García, Diego A. León; Ferro, Gaetana; Cruz, Inês; Reyes, Ivonne Johana Cárdenas; García, Joel Salazar-Mendiguchía; Larrañaga‐Moreira, José M.; Ochoa, Juan Pablo; Palomino-Doza, Julián; Romero, Luis de la Higuera; Cicerchia, Marcos; Córdoba, María Alejandra; Peña-Peña, María Luisa; Brogger, M N; Loureiro, Marília; Jimenez, Maria; Quesada, Raquel Bilbao; Franco‐Gutiérrez, Raúl; Hernandez, S Garcia; Ripoll‐Vera, Tomás; Fernández, Xusto; Azevedo, Olga; Pavía, Pablo García; Lopes, Luís Rocha; Ortiz, Martín; Brito, Dulce; Barriales‐Villa, Roberto; Iglesias, Lorenzo Monserrat

doi:10.1016/j.rec.2021.01.001

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Patients are generally diagnosed in their teens or early adulthood, although still significantly younger overall compared to patients with HCM with heterozygous variants in sarcomeric genes: median (IQR) 25.0 (13.0–35.0) years versus 37.5 (23.6–49.8) years in the SHaRe registry ( P = 1 × 10 −10 , two-tailed z -test) 15 . The later age of onset observed for TPM1 reflects the fact that four of six biallelic cases had the same Spanish founder variant (p.Arg21Leu), which is associated with a relatively mild and late-onset disease course 24 . Although the other genes display a broadly similar age at onset and outcome profiles, they can be distinguished by other features.…”

Section: Resultsmentioning

confidence: 96%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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Section: Resultsmentioning

confidence: 96%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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“…Such findings impose a reconsideration of what really matters in the transcriptome changes. Interestingly, while Tpm1 is one of the main hypertrophic cardiomyopathy genes [ 47 ], Tpm4 is known for its inhibitory effect on actin polymerization [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

Theory and Applications of the (Cardio) Genomic Fabric Approach to Post-Ischemic and Hypoxia-Induced Heart Failure

Iacobaş

2022

JPM

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The genomic fabric paradigm (GFP) characterizes the transcriptome topology by the transcripts’ abundances, the variability of the expression profile, and the inter-coordination of gene expressions in each pathophysiological condition. The expression variability analysis provides an indirect estimate of the cell capability to limit the stochastic fluctuations of the expression levels of key genes, while the expression coordination analysis determines the gene networks in functional pathways. This report illustrates the theoretical bases and the mathematical framework of the GFP with applications to our microarray data from mouse models of post ischemic, and constant and intermittent hypoxia-induced heart failures. GFP analyses revealed the myocardium priorities in keeping the expression of key genes within narrow intervals, determined the statistically significant gene interlinkages, and identified the gene master regulators in the mouse heart left ventricle under normal and ischemic conditions. We quantified the expression regulation, alteration of the expression control, and remodeling of the gene networks caused by the oxygen deprivation and determined the efficacy of the bone marrow mono-nuclear stem cell injections to restore the normal transcriptome. Through the comprehensive assessment of the transcriptome, GFP would pave the way towards the development of personalized gene therapy of cardiac diseases.

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“…Still, in a specific population, founder variants may account for a substantial portion of disease-causing variants among probands [ 3 , 4 ]. So far, HCM-causing founder variants have been reported in MYBPC3 [ 4 ], MYH7 [ 5 ], TPM1 [ 6 , 7 ], JHP2 [ 8 ], and TNNI3 [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

Vodnjov,

Toplišek,

Maver

et al. 2023

PLoS ONE

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Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.

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Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant

Cited by 4 publications

References 33 publications

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Theory and Applications of the (Cardio) Genomic Fabric Approach to Post-Ischemic and Hypoxia-Induced Heart Failure

A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans–A cohort study

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