Publications by authors named "Richard Redon"

Background: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.

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  • Brugada syndrome (BrS) is a hereditary cardiac disorder linked to sudden death in young adults, particularly prevalent in Southeast Asia, with certain genetic variants associated with the condition.
  • Researchers conducted genome sequencing on individuals with BrS and matched controls in Thailand to find rare noncoding variants that are more common in BrS patients.
  • A specific rare variant was identified that disrupts a transcription factor binding site, causing reduced gene expression and reduced sodium current in heart cells, contributing to the high prevalence of BrS in the region and identifying at-risk individuals.
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  • The study investigates the demographic history of France using genotype datasets from individuals in Northern France, revealing significant population structure and differentiation in regions like Brittany and the Loire basin.
  • The research highlights a connection between the ancestry of local populations and genetic variations, particularly indicating a distinction in shared ancestry related to Neolithic and steppe populations.
  • Findings suggest the necessity of studying local demographics to better comprehend the distribution of genetic variants and their role in the prevalence of diseases among populations in Brittany and neighboring areas.
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  • * These disorders result in developmental issues, particularly affecting neural development and causing physical abnormalities like craniofacial defects and heart malformations.
  • * The paper suggests that neural crest cells, which play a crucial role in forming craniofacial structures and heart components, may be particularly affected by disruptions in protein homeostasis, urging further research for potential treatments.
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Background And Aims: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries.

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  • - The study investigates the role of 3D chromatin organization in gene regulation and its link to human Mendelian diseases, particularly focusing on a new cardiac condition found in 7 families caused by a deletion of CTCF binding sites on chromosome 4q25.
  • - This deletion results in the fusion of topologically associating domains (TADs) and alters chromatin structure, affecting the expression of the PITX2 gene, which is critical for heart function.
  • - Using a mouse model that mimics the human genetic deletion, researchers observed changes in PITX2 expression in the heart, leading to the conclusion that TAD remodeling due to CTCF site deletion is responsible for a novel autosomal dominant Mend
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Mutations in the DES gene, which encodes the intermediate filament desmin, lead to desminopathy, a rare disease characterized by skeletal muscle weakness and different forms of cardiomyopathies associated with cardiac conduction defects and arrhythmias. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying the DES p.R406W mutation, and employed CRISPR/Cas9 to rectify the mutation in the patient's hiPSC line and introduced the mutation in an hiPSC line from a control individual unrelated to the patient.

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Imputation servers offer the exclusive possibility to harness the largest public reference panels which have been shown to deliver very high precision in the imputation of European genomes. Many studies have nonetheless stressed the importance of 'study specific panels' (SSPs) as an alternative and have shown the benefits of combining public reference panels with SSPs. But such combined approaches are not attainable when using external imputation servers.

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  • * Researchers evaluated 22 patients with recurrent ventricular arrhythmias, finding that all had abnormal substrate in the RV, while 45% also exhibited abnormalities in the LV epicardium.
  • * Results show that patients with LV abnormalities had longer arrhythmia histories and higher rates of SCN5A mutations, suggesting a significant link between these substrates and genetic factors in BrS.
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Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia.

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Background: In first-degree relatives of patients with aneurysmal subarachnoid hemorrhage (aSAH), the risk of an intracranial aneurysm can be predicted at initial screening but not at follow-up screening. We aimed to develop a model for predicting the probability of a new intracranial aneurysm after initial screening in people with a positive family history of aSAH.

Methods: In a prospective study, we obtained data from follow-up screening for aneurysms of 499 subjects with ≥2 affected first-degree relatives.

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Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls.

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Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves.

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Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls.

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Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured.

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Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated.

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Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.

Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).

Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.

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  • Intellectual disability (ID) is often linked to genetic defects, with this study identifying 14 SEMA6B gene variants in patients diagnosed with ID but without epilepsy.
  • The researchers conducted experiments showing that these SEMA6B variants affect protein localization and lead to reduced spine density in both cell cultures and chicken embryos, indicating a significant role in neuron development.
  • The findings broaden the understanding of SEMA6B-related conditions, suggesting it is also a contributor to ID, expanding its clinical significance beyond previously known associations with epilepsy.
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Background: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns.

Methods: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands.

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  • Brugada syndrome (BrS) is a serious heart condition linked to sudden death in young adults, with few known genetic factors beyond the SCN5A gene.
  • A large study involving 2,820 BrS cases and 10,001 controls revealed 21 genetic signals across 12 locations, suggesting a strong genetic component to the disorder.
  • Key findings highlight the importance of transcription regulation in BrS development and introduce microtubule-related mechanisms that affect the expression of a key cardiac protein, shedding light on the disorder's genetic and molecular basis.
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Background: Persons with a positive family history of aneurysmal subarachnoid hemorrhage are at increased risk of aneurysmal subarachnoid hemorrhage. Preventive screening for intracranial aneurysms (IAs) in these persons is cost-effective but not very efficient. We aimed to develop and externally validate a model for predicting the probability of an IA at first screening in persons with a positive family history of aneurysmal subarachnoid hemorrhage.

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  • Nuclear deubiquitinase BAP1 is a crucial part of protein complexes that help regulate gene transcription by reversing the ubiquitination of histone 2A, and its loss can lead to cancer.
  • This study identified 11 rare, de novo germline BAP1 variants associated with a unique neurodevelopmental disorder, where most of these variants demonstrated a loss-of-function effect.
  • Functional analyses showed these variants impaired histone modifications, leading to significant changes in chromatin states and contributing to dysregulation of genes essential for development.
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Four human induced pluripotent stem cell (hiPSC) lines have been generated from healthy control European donors, and validated. This resource represents a useful tool for stem cell-based research, as references for developmental studies and disease modeling linked to any type of human tissue and organ, in an ethnical-, sex- and age-matched context. They providea reliable in-vitro model for single cell- and tissue-based investigations, and are also a valuable tool for genome editing-based studies.

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Catecholamine-induced QT prolongation (CIQTP) is an inherited cardiac disease characterized by a normal baseline ECG and a risk of sudden cardiac death by ventricular arrhythmia due to a QT prolongation that only appears during catecholergic stimulation, especially mental stress. Induced pluripotent stem cells (hiPSCs) were generated from peripheral blood mononuclear cells collected from two CIQTP-affected patients from two different families. These two hiPSC lines are a valuable model to study biological alterations due to CIQTP.

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