Atteintes ventriculaires droites liées aux laminopathies : prévalence et pronostic dans une cohorte de 138 patients

Introduction: Laminopathies are rare genetic diseases, with various clinical manifestations. Cardiac involvement may include conduction disorders, rhythm disorders and cardiomyopathy with left ventricular dysfunction. Right ventricular dysfunction is correlated with a poor prognosis in other cardiopathies. Our aim is to study the prevalence of right ventricular involvement in laminopathies and the influence on the outcome. Methods and Results: We followed a 138 patients cohort who carried LMNA gene mutations. 18 patients (13%) presented right ventricular systolic dysfunction with clinical heart failure, among which 9 (6.5%) had no associated left ventricular dysfunction. Right ventricular involvement was associated with the presence of truncating mutations (44% vs 22%, p = 0.04) and extracardiac manifestations (94.4% vs 72.5%, p=0.04); Follow-up revealed more deaths (44% vs 17%, p <0.001), end-stage heart failure (56% vs 11%, p<0.001), non-sustained ventricular tachycardia (50% vs 18%, p <0.001), sustained ventricular tachycardia (56% vs. 17%, p<0.001), supraventricular tachycardias (94% vs 49%, p <0.001), and sinus dysfunction (33% vs. 7%, p<0.001). Conclusion: Right ventricular dysfunction may occur in laminopathies, even without left ventricular dysfunction, and is associated with a poor prognosis and a high risk of rapid evolution to end-stage heart failure. Conduction disorders and arrhythmias were particularly frequent. Lamin mutation carriers should have a regular evaluation of their right ventricular function.Objectifs : Les laminopathies sont des maladies génétiques rares, regroupant des phénotypes divers. Les atteintes cardiaques connues se caractérisent par des troubles conductifs, des troubles du rythme, et des cardiomyopathies avec dysfonction ventriculaire gauche. Dans la plupart des autres cardiopathies, une atteinte ventriculaire droite est de mauvais pronostic. Nous avons voulu étudier la prévalence d’une atteinte ventriculaire droite dans les laminopathies et son impact sur le pronostic. Méthodes et résultats : Nous avons suivi une cohorte de 138 patients porteurs de mutations dans le gène LMNA. Une dysfonction systolique et une insuffisance cardiaque droite étaient présentes chez 18 patients (13%), dont 9 (6.5%) sans dysfonction gauche associée. Une atteinte ventriculaire droite était associée à la présence de mutations tronquantes (44% vs 22%, p=0,04) et d’une atteinte extracardiaque de la laminopathie (94,4% vs 72,5%, p=0,04), et au cours du suivi à significativement plus de décès (44% vs 17%, p<0,001), d’insuffisance cardiaque terminale (56% vs 11%, p<0,001), de tachycardies ventriculaires non soutenues (50% vs 18%, p<0,001) et soutenues (56% vs 17%, p<0,001), de tachycardies supraventriculaires (94% vs 49%, p<0,001), et de dysfonction sinusale (33% vs 7%, p<0,001). Conclusion : les laminopathies peuvent se compliquer d’une dysfonction ventriculaire droite, y compris sans atteinte ventriculaire gauche associée. Celle-ci est de mauvais pronostic avec un haut risque d’évolution rapide vers une insuffisance cardiaque terminale. Elle se complique fréquemment de troubles du rythme et de conduction. Elle doit être dépistée systématiquement lors du suivi de ces patients

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

International audienceInterindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men