CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

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

Interindividual 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-w (IFN-w) (13 patients), against the 13 types of IFN-a (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

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Inflamación relacionada con angiopatía amiloide: características clínicas y respuesta al tratamiento en una serie de casos

Resumen: Introducción: La inflamación relacionada con la angiopatía amiloide es una entidad caracterizada por una respuesta inflamatoria alrededor de los depósitos de beta amiloide de la microcirculación cerebral. Métodos: Revisión retrospectiva de una serie de pacientes con inflamación relacionada con angiopatía amiloide, que cumplieran criterios clínico-radiológicos o con diagnóstico histopatológico confirmado. Resultados: Se incluyeron siete pacientes, cinco varones, con edad media de 79 años. El inicio fue agudo o subagudo en seis de los casos. La clínica más frecuente fue deterioro cognitivo (n = 6), alteraciones de conducta (n = 5), crisis epilépticas (n = 5), focalidad neurológica (n = 4) y cefalea (n = 2). El líquido cefalorraquídeo fue anormal en tres de cinco casos (pleocitosis linfocitaria e hiperproteinorraquia). Las imágenes de resonancia magnética cerebral más frecuentes consistieron en microhemorragias (n = 7), hiperintensidades subcorticales en secuencia T2-FLAIR (n = 7) y realce leptomeníngeo (n = 6). La afectación fue bilateral en tres de los casos, con predominio en regiones parieto-occipitales (n = 5). Se realizó una tomografía por emisión de positrones (PET) de amiloide en dos pacientes, resultando positiva en uno. Se obtuvo la confirmación histopatológica mediante una biopsia en dos de los casos. Todos los sujetos recibieron tratamiento inmunosupresor, objetivándose una respuesta clínica y radiológica inicial favorable, con recaída radiológica en dos de los casos tras la retirada del tratamiento, y mejorando tras la reinstauración. Conclusiones: El diagnóstico resulta imprescindible de cara a iniciar un tratamiento precoz, ya que ha demostrado mejorar el pronóstico y disminuir las recurrencias. Si bien el diagnóstico definitivo es histopatológico, los criterios clínico-radiológicos permiten el diagnóstico de esta entidad sin necesidad de biopsia. Abstract: Introduction: Cerebral amyloid angiopathy–related inflammation (CAA-ri) is an entity characterised by an inflammatory response to β-amyloid deposition in the walls of cerebral microvessels. Methods: We conducted a retrospective review of a series of patients with a diagnosis of CAA-ri according to histopathological study findings or clinical-radiological diagnostic criteria. Results: The study included 7 patients (5 men) with a mean age of 79 years. Disease onset was acute or subacute in 6 patients. The most frequent symptoms were cognitive impairment (n = 6), behavioural alterations (n = 5), epileptic seizures (n = 5), focal neurological signs (n = 4), and headache (n = 2). Cerebrospinal fluid was abnormal in 3 patients (lymphocytic pleocytosis and high protein levels). The most frequent MRI findings were microbleeds (n = 7), subcortical white matter hyperintensities on T2-FLAIR sequences (n = 7), and leptomeningeal enhancement (n = 6). Lesions were bilateral in 3 patients and most frequently involved the parieto-occipital region (n = 5). Amyloid PET studies were performed in 2 patients, one of whom showed pathological findings. Two patients underwent brain biopsy, which confirmed diagnosis. All patients received immunosuppressive therapy. An initially favourable clinical-radiological response was observed in all cases, with 2 patients presenting radiological recurrence after treatment withdrawal, with a subsequent improvement after treatment was resumed. Conclusions: Early diagnosis of CAA-ri is essential: early treatment has been shown to improve prognosis and reduce the risk of recurrence. Although a histopathological study is needed to confirm diagnosis, clinical-radiological criteria enable diagnosis without biopsy

Worldwide Effects of Coronavirus Disease Pandemic on Tuberculosis Services, January\u2013April 2020

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

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