Browsing by Author "Poli, Cecilia"
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Item Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency(2020) Saettini, Francesco; Poli, Cecilia; Vengoechea, Jaime; Bonanomi, Sonia; Orellana, Julio C.; Fazio, Grazia; Rodriguez, Fred H.; Noguera, Loreani; Booth, Claire; Jarur-Chamy, Valentina; Shams, Marissa; Iascone, María; Vukic, Maja; Gasperini, Serena; Quadri, Manuel; Barroeta Seijas, Amairelys; Rivers, Elizabeth; Mauri, Mario; Badolato, Raffaele; Cazzaniga, Gianni; Bugarin, Cristina; Gaipa, Giuseppe; Kroes, Wilma G. M.; Moratto, Daniele; Oostaijen-Ten Dam, Monique M. van; Baas, Frank; Maarel, Silvère van der; Piazza, Rocco; Coban-Akdemir, Zeynep H.; Lupski, James R.; Yuan, Boi; Daxinger, Lucia; Biondi, Andrea; Chinn, Ivan K.Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated three novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound heterozygous variants in the gene for Folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and PI3K/AKT pathway, was impaired. These defects recapitulated the Fnip1 -/- animal model. Moreover, we identified either uniparental disomy or copy number variants [CNV] in two patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.Publication Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C(2022) Burbelo, Peter; Castagnoli, Riccardo; Shimizu, Chisato; Delmonte, Ottavia; Dobbs, Kerry; Discepolo, Valentina; Lo Vecchio, Andrea; Guarino, Alfredo; Licciardi, Francesco; Ramenghi, Ugo; Rey, Emma; Vial, Cecilia; Marseglia, Gian; Licari, Amelia; Montagna, Daniela; Rossi, Camillo; Montealegre, Gina; Barron, Karyl; Warner, Blake; Chiorini, John; Espinosa, Yazmin; Noguera, Loreani; Dropulic, Lesia; Truong, Meng; Gerstbacher, Dana; Mató, Sayonara; Kanegaye, John; Tremoulet, Adriana; Pediatric Emergency Medicine Kawasaki Group; Eisenstein, Eli; Su, Helen; Imberti, Luisa; Poli, Cecilia; Burns, Jane; Notarangelo, Luigi; Cohen, JeffreyThe antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.Item Characterizing the molecular mechanisms of immune dysregulation in proteasome-related interferonopathies and other autoinflammatory diseases(Universidad del Desarrollo. Facultad de Medicina, 2022-01) Jarur Chamy, Valentina Lucía; Poli, Cecilia; Carrión Arriagada, FlavioMonogenic Immune Dysregulatory Syndromes are rare life-threatening diseases in which a single genetic defect causes global immune dysregulation manifested by either immunodeficiency, autoinflammation or autoimmunity in a nonexclusive way. Particularly, Proteasome-associated autoinflammatory Syndromes (PRAAS) are a group of Immune Dysregulatory Syndromes in which loss of function variants in proteasome subunits cause Type I IFN-mediated autoinflammation, ulcerative skin lesions and lipodystrophy through still unknown mechanisms. Proteasome-related Autoinflammation and Immunodeficiency Disease (PRAID) is a novel PRAAS caused by pathogenic variants in POMP, a proteasome assembly chaperone. PRAID patients present PRAAS-like clinical manifestations but also, they have an increased susceptibility to pneumocystis and mycobacterial infections, delineating a combined immunodeficiency that paradoxically co-exist with the autoinflammatory features in this Immune Dysregulatory Syndrome. PRAID patients present low expression of proinflammatory cytokines in T cells in vitro and NFkB deficiency is a known cause of immunodeficiency. In this regard, the proteasome plays a critical role in the activation of NFkB pathway that could be underlying the immunodeficiency in PRAID patients. Conversely, here we identified a sustained up-regulation of NFkB signaling in PRAID patients, suggesting the contribution of NFkB to the Type I IFN-mediated autoinflammatory phenotype in PRAID patients. Additionally, we identified that Type I IFN and NFkB dysregulation in PRAID patients are mediated by the Protein Kinase R (PKR), a cytosolic RNA sensor that triggers Type I IFN and NF-kB signaling upon activation. The mechanisms by which PKR is up-regulated in PRAID still remains elusive and a constitutive activation of PKR does not explain the immunodeficiency in these patients. In this regard, we demonstrated that pathogenic variants in POMP causing PRAID impair the interaction of the chaperone POMP with the immune-proteasome catalytic subunits suggesting a potential role of impaired immune proteasome assembly in the combined immunodeficiency of PRAID patients. PRAID supports the notion of Immune Dysregulatory Syndromes as complex immune-related phenotypes with more than one compromised pathway, reinforcing the relevance of a complete characterization of the pro-inflammatory environment in each genetically-determined disease. In this regard, we used the Type I IFN Signature previously standardized in PRAID patient-derived cells as a translational application for the diagnosis of Immune Dysregulatory patients with clinical features compatible with Type I IFN dysregulation. Here, we empirically demonstrated the relevance of Type I IFN evaluation through the Type I IFN signature for the genetic interpretation and functional validation of novel genetic candidates in patients with type I IFN dysregulation with and without proteasome dysfunction.Item Clinical, neuroimaging, and molecular spectrum of TECPR2‐associated hereditary sensory and autonomic neuropathy with intellectual disability(2021) Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Brösse, Ines; Schubert, Susanna; O'Grady, Lauren; Zech, Michael; Srivastava, Siddharth; Sweetser, David A.; Dincer, Yasemin; Mall, Volker; Winkelmann, Juliane; Behrends, Christian; Darras, Basil T.; Graham, Robert J.; Jayakar, Parul; Byrne, Barry; Bar‐Aluma, Bat El; Haberman, Yael; Szeinberg, Amir; Aldhalaan, Hesham M.; Hashem, Mais; Tenaiji, Amal Al; Ismayl, Omar; Al Nuaimi, Asma E.; Maher, Karima; Ibrahim, Shahnaz; Khan, Fatima; Houlden, Henry; Ramakumaran, Vijayalakshmi S.; Pagnamenta, Alistair T.; Posey, Jennifer E.; Lupski, James R.; Tan, Wen‐Hann; ElGhazali, Gehad; Herman, Isabella; Muñoz, Tatiana; Repetto, Gabriela; Seitz, Angelika; Krumbiegel, Mandy; Poli, Cecilia; Kini, Usha; Efthymiou, Stephanie; Meiler, Jens; Maroofian, Reza; Alkuraya, Fowzan S.; Jamra, Rami Abou; Popp, Bernt; Ben‐Zeev, Bruria; Ebrahimi‐Fakhari, DariusBi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐ sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/ treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies.Item Compromiso cardiovascular en pacientes con Síndrome Inflamatorio Pediátrico Multisistémico, asociado a infección por SARS-CoV- 2(2020) Álvarez, Patricia; Acevedo, Valeria; Valenzuela, María Lidia; Montesae, Vicente; Campos, Carolina; Koch, Katherine; González, Soledad.; Poli, Cecilia; Verdugo, Patricia; Cofré, Fernanda; Mackenney, Jorge; Tapia, LorenaIntroduction: Pediatric Multisystemic Inflammatory Syndrome (PIMS) has emerged as a new disease in children, secondary to SARSCoV-2 infection. It is characterized by multi-organ involvement with elevated inflammatory parameters and severe clinical manifestations, the heart being the organ most severely involved. Objective: to describe the clinical and laboratory characteristics of 23 patients diagnosed with PIMS with cardiovascular involvement hospitalized in a single center. Method: We conducted a retrospective study in which we analyzed the clinical and laboratory findings along with the cardiovascular manifestations presented by these patients. Results: 23/29 patients with PIMS and cardiovascular involvement were selected, 78% had digestive and mucocutaneous manifestations. Cardiovascular manifestations consisted of KawasakiKawasaki like syndrome without coronary involvement in 15/23 (65%) and coronary involvement in 3 (13%). Nine patients developed shock (39%), 8 (35%) myocardial injury in and 13 (56%) pericardial effusion.. Heart rhythm disorders were observed in 6 patients (26%). The main therapy was immunoglobulin and corticosteroids. 18 /23 required management in intermediate and/or intensive care unit. 70% of patients recovered from cardiovascular involvement before discharge. Conclusion: Cardiovascular involvement in PIMS is the most frequent complication of this disease, but it is associated with severe immunological and hematological manifestations, which makes necessary a multidisciplinary treatment for a better managementItem Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)(Frontiers, 2019) Ebstein, Frédéric; Poli, Cecilia; Studencka-Turski, Maja; Krüger, ElkeType I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.Item Coronavirus disease 2019 in patients with inborn errors of immunity: An international study(2022) Meyts, Isabelle; Bucciol, Giorgia; Quinti, Isabella; Neven, Bénédicte; Fischer, Alain; Seoane, Elena; Lopez-Granados, Eduardo; Gianelli, Carla; Robles-Marhuenda, Angel; Jeandel, Pierre-Yves; Paillard, Catherine; Sankaran, Vijay G.; Demirdag, Yesim Yilmaz; Lougaris, Vassilios; Aiuti, Alessandro; Plebani, Alessandro; Milito, Cinzia; Dalm, Virgil Ash; Guevara-Hoyer, Kissy; Sánchez-Ramón, Silvia; Bezrodnik, Liliana; Barzaghi, Federica; González-Granado, Luis Ignacio; Hayman, Grant R.; Uzel, Gulbu; Mendonça, Leonardo Oliveira; Agostini, Carlo; Spadaro, Giuseppe; Badolato, Raffaele; Soresina, Annarosa; Vermeulen, Francois; Bosteels, Cedric; Lambrecht, Bart N.; Keller, Michael; Mustillo, Peter J.; Abraham, Roshini S.; Gupta, Sudhir; Ozen, Ahmet; Karakoc-Aydiner, Elif; Baris, Safa; Freeman, Alexandra F.; Yamazaki-Nakashimada, Marco; Scheffler-Mendoza, Selma; Espinoza Padilla, Sara; Gennery, Andrew R.; Jolles, Stephen; Espinosa, Yazmin; Poli, Cecilia; Fieschi, Claire; Hauck, Fabian; Cunningham-Rundles, Charlotte; Mahlaouie, Nizar; Sullivan, Kathleen E.; Tangye, Stuart G.; IUIS Committee of Inborn Errors of Immunity;Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.Publication Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort(2022) Rey, Emma; Espinosa, Yazmin; Astudillo, Camila; Jimena, Lina; Hormazábal, Juan; Noguera, Loreani; Cofré, Fernanda; Piñera, Cecilia; González, Ricardo; Bataszew, Alexander; Muñoz, Paula; Benadof, Dona; Álvarez, Patricia; Acevedo, Valeria; Vial, Pablo; Vial, Cecilia; Poli, CeciliaBackground: Multisystemic inflammatory syndrome in children (MIS-C) is a life-threatening disease that occurs 2-5 weeks after severe acute respiratory syndrome coronavirus 2 exposure and is characterized by severe multisystemic inflammation. Early recognition of MIS-C is key to prognosis; therefore, establishing clinical and laboratory biomarkers that predict complications is urgently needed. Objective: We characterized the immune response and clinical features of patients with acute MIS-C and determined biomarkers of disease in a cohort of 42 Latin American patients. Methods: Immune characterization was performed using flow cytometry from peripheral mononuclear cells and severe acute respiratory syndrome coronavirus 2-specific humoral and cellular response was performed using flow cytometry, enzyme-linked immunospot, enzyme-linked immunosorbent assay, and neutralizing antibody assays. Results: MIS-C is characterized by robust T-cell activation and cytokine storm. We uncovered that while C-X-C motif chemokine ligand (CXCL) 9, IL-10, CXCL8, CXCL10, IL-6, and IL-18 are significantly elevated in patients with shock, while CCL5 was increased in milder disease. Monocyte dysregulation was specifically associated with KD-like MIS-C. Interestingly, MIS-C patients show a natural killer cell degranulation defect that is persistent after 6 months of disease presentation, suggesting it could underlie disease susceptibility. Most MIS-C had gastrointestinal involvement, and higher levels of neopterin were identified in their stools, potentially representing a biomarker of intestinal inflammation in MIS-C. Severe acute respiratory syndrome coronavirus 2-specific cellular response and neutralizing antibodies were identifiable in convalescent MIS-C patients, suggesting sustained immunity. Conclusion: Clinical characterization and comprehensive immunophenotyping of Chilean MIS-C cohort provide valuable insights in understanding immune dysregulation in MIS-C and identify relevant biomarkers of disease that could be used to predict severity and organ involvement.Item Espectro clínico de la infección en niños por virus SARS-CoV-2 en un centro de referencia pediátrico en plena pandemia. Reporte del Comité Clínico COVID, Hospital de Niños Roberto del Río, Santiago Chile(2020) Cofré, Fernanda; Mackenney, Jorge; Poli, Cecilia; Riquelme, Maryel; Carvajal, Cristian; Álvarez, Patricia; Acevedo, Valeria; Valenzuela, M. Lidia; Verdugo, Patricia; Varas, Mónica; Tapia, LorenaIntroducción: La infección por virus SARS-CoV-2 responsable de la pandemia actual, es una entidad clínica y fisiopatológica nueva y en desarrollo, cuyo control aún es incierto mientras no contemos con una vacuna efectiva y de distribución universal. Descrita inicialmente como una enfermedad respiratoria mayoritariamente de adultos, los niños también pueden enfermar y se ha visto que en ellos las manifestaciones clínicas de enfermedad suelen diferir a las de los adultos expresándose como cuadros benignos en su mayoría. Si requieren hospitalización o algún tipo de asistencia, el cuadro se resuelve con tratamiento de soporte y sin complicaciones, mayoritariamente. Sin embargo, en el síndrome inflamatorio multisistémico asociado a COVID-19 (SIM-C) es de vital importancia la sospecha precoz y la derivación a un centro de alta complejidad para otorgar el soporte y tratamiento adecuado para lograr una buena y adecuada sobrevida. Objetivo: Describir el espectro clínico de enfermedad por virus SARSCoV-2 en un centro de referencia pediátrico con la pandemia aún en desarrollo. Método: Se presenta la casuística de 537 pacientes con infección por SARS-CoV-2 atendidos entre marzo 1 y julio 15, 2020, con descripción de aquellos que fueran hospitalizados. Resultados: 127 (23%) de ellos fueron internados y de éstos 69% sintomáticos. Veintiséis pacientes (20%) de los hospitalizados presentaron SIM-C y sólo uno falleció por complicaciones de sus patologías de base.Item Espectro clínico de la infección en niños por virus SARS-CoV-2 en un centro de referencia pediátrico en plena pandemia. Reporte del Comité Clínico COVID, Hospital de Niños Roberto del Río, Santiago Chile(2020) Cofré, Fernanda; Mackenney, Jorge; Poli, Cecilia; Riquelme, Maryel; Carvajal, Cristian; Alvarez, Patricia; Acevedo, Valeria; Valenzuela, M. Lidia; Verdugo, Patricia; Varas, Mónica; Tapia, LorenaIntroducción: La infección por virus SARS-CoV-2 responsable de la pandemia actual, es una entidad clínica y fisiopatológica nueva y en desarrollo, cuyo control aún es incierto mientras no contemos con una vacuna efectiva y de distribución universal. Descrita inicialmente como una enfermedad respiratoria mayoritariamente de adultos, los niños también pueden enfermar y se ha visto que en ellos las manifestaciones clínicas de enfermedad suelen diferir a las de los adultos expresándose como cuadros benignos en su mayoría. Si requieren hospitalización o algún tipo de asistencia, el cuadro se resuelve con tratamiento de soporte y sin complicaciones, mayoritariamente. Sin embargo, en el síndrome inflamatorio multisistémico asociado a COVID-19 (SIM-C) es de vital importancia la sospecha precoz y la derivación a un centro de alta complejidad para otorgar el soporte y tratamiento adecuado para lograr una buena y adecuada sobrevida. Objetivo: Describir el espectro clínico de enfermedad por virus SARS-CoV-2 en un centro de referencia pediátrico con la pandemia aún en desarrollo. Método: Se presenta la casuística de 537 pacientes con infección por SARS-CoV-2 atendidos entre marzo 1 y julio 15, 2020, con descripción de aquellos que fueran hospitalizados. Resultados: 127 (23%) de ellos fueron internados y de éstos 69% sintomáticos. Veintiséis pacientes (20%) de los hospitalizados presentaron SIM-C y sólo uno falleció por complicaciones de sus patologías de base.Item Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.(Frontiers, 2019) Staines, Aidé; Chinn, Ivan; Alaez-Versón, Carmen; Yamazaki-Nakashimada, Marco; Carrillo-Sánchez, Karol; García-Cruz, María de la Luz; Poli, Cecilia; González Serrano, Edith; Medina, Edgar; Muzquiz, David; Forbes, Lisa; Espinosa-Rosales, Francisco; Espinosa-Padilla, Sara; Orange, Jordan; Lugo, SaulDNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.Item First Report of Tocilizumab Use in a Cohort of Latin American Patients Hospitalized for Severe COVID-19 Pneumonia(2020) Valenzuela, Omar; Ibáñez, Sebastián; Poli, Cecilia; Roessler, Patricia; Aylwin, Mabel; Roizen, Gigia; Iruretagoyena, Mirentxu; Agar, Vivianne; Donoso, Javiera; Fierro, Margarita; Montes, José MiguelIntroduction/objectives: An interleukin-6 inhibition strategy could be effective in selected COVID-19 patients. The objective is to present our experience of tocilizumab use in patients with severe COVID-19. Methods: Observational retrospective cohort study. Hospitalized patients were evaluated by our multidisciplinary team for eventual use of tocilizumab. Patients with progressive ventilatory impairment and evidence of a hyperinflammatory state despite usual treatment received tocilizumab 8 mg/kg intravenous (maximum dose 800 mg), in addition to standard treatment. The use and time of use of mechanical ventilation (MV), the change of the Alveolar-arterial (A-a) gradient, of the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and of inflammation laboratory parameters after 72 h of tocilizumab use was evaluated. Results: 29 patients received tocilizumab. 93.1% were men, 37.9% were obese, and 34.5% had hypertension. Of the 20 patients who were not on MV when receiving tocilizumab, 11 required non-invasive MV, for an average of 5 days, and one of them required intubation. A-a gradient, PaO2/FiO2, and inflammation parameters improved significantly. A better lymphocyte count, which improved significantly after tocilizumab use, was significantly associated with less use of MV. Five patients presented positive culture samples after tocilizumab, three being of clinical significance. A lower lymphocyte count was associated with having a positive culture. No other significant adverse events were seen. Conclusion: Our study suggests the utility and shows the safety of tocilizumab use in COVID-19 patients who have respiratory failure and evidence of hyperinflammation. Lymphocyte improvement was a predictor of good response.Item First Report of Tocilizumab Use in a Cohort of Latin American Patients Hospitalized for Severe COVID-19 Pneumonia(2020) Valenzuela, Omar; Ibáñez, Sebastián; Poli, Cecilia; Roessler, Patricia; Aylwin, Mabel; Roizen, Gigia; Iruretagoyena, Mirentxu; Agar, Vivianne; Donoso, Javiera; Fierro, Margarita; Montes, JoséIntroduction/objectives: An interleukin-6 inhibition strategy could be effective in selected COVID-19 patients. The objective is to present our experience of tocilizumab use in patients with severe COVID-19. Methods: Observational retrospective cohort study. Hospitalized patients were evaluated by our multidisciplinary team for eventual use of tocilizumab. Patients with progressive ventilatory impairment and evidence of a hyperinflammatory state despite usual treatment received tocilizumab 8 mg/kg intravenous (maximum dose 800 mg), in addition to standard treatment. The use and time of use of mechanical ventilation (MV), the change of the Alveolar-arterial (A-a) gradient, of the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and of inflammation laboratory parameters after 72 h of tocilizumab use was evaluated. Results: 29 patients received tocilizumab. 93.1% were men, 37.9% were obese, and 34.5% had hypertension. Of the 20 patients who were not on MV when receiving tocilizumab, 11 required non-invasive MV, for an average of 5 days, and one of them required intubation. A-a gradient, PaO2/FiO2, and inflammation parameters improved significantly. A better lymphocyte count, which improved significantly after tocilizumab use, was significantly associated with less use of MV. Five patients presented positive culture samples after tocilizumab, three being of clinical significance. A lower lymphocyte count was associated with having a positive culture. No other significant adverse events were seen. Conclusion: Our study suggests the utility and shows the safety of tocilizumab use in COVID-19 patients who have respiratory failure and evidence of hyperinflammation. Lymphocyte improvement was a predictor of good response.Item Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis(2018) Chinn, Ivan K.; Eckstein, Olive S.; Peckham-Gregory, Erin C.; Goldberg, Baruch R.; Forbes, Lisa R.; Nicholas, Sarah K.; Mace, Emily M.; Vogel, Tiphanie P.; Abhyankar, Harshal A.; Diaz, Maria I.; Heslop, Helen E.; Krance, Robert A.; Martinez, Caridad A.; Nguyen, Trung C.; Bashir, Dalia A.; Goldman, Jordana R.; Stray-Pedersen, Asbjørg; Pedroza, Luis A.; Poli, Cecilia; Aldave-Becerra, Juan C.; McGhee, Sean A.; Al-Herz, Waleed; Chamdin, Aghiad; Coban-Akdemir, Zeynep H.; Jhangiani, Shalini N.; Muzny, Donna M.; Cao, Tram N.; Hong, Diana N.; Gibbs, Richard A.; Lupski, James R.; Orange, Jordan S.; McClain, Kenneth L.; Allen, Carl E.The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.Item Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders(2022) Forbes, Lisa R.; Eckstein, Olive S.; Gulati, Nitya; Peckham-Gregory, Erin C.; Ozuah, Nmazuo W.; Lubega, Joseph; El-Mallawany, Nader K.; Agrusa, Jennifer E.; Poli, Cecilia; Vogel, Tiphanie P.; Chaimowitz, Natalia S.; Rider, Nicholas L.; Mace, Emily M.; Orange, Jordan S.; Caldwell, Jason W.; Aldave-Becerra, Juan C.; Jolles, Stephen; Saettini, Francesco; Chong, Hey J.; Stray-Pedersen, Asbjorg; Heslop, Helen E.; Kamdar, Kala Y.; Rouce, R. Helen; Muzny, Donna M.; Jhangiani, Shalini N.; Gibbs, Richard A.; Coban-Akdemir, Zeynep H.; Lupski, James R.; McClain, Kenneth L.; Allen, Carl E.; Chinn, Ivan K.Background: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. Objective: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. Methods: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. Results: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. Conclusions: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.Item HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease(2020) Cook, Sarah A; Comrie, William A; Poli, Cecilia; Similuk, Morgan; Oler, Andrew J; Faruqi, Aiman J; Kuhns, Douglas B; Yang, Sheng; Vargas-Hernández, Alexander; Carisey, Alexandre F; Fournier, Benjamin; Anderson, D Eric; Price, Susan; Smelkinson, Margery; Abou Chahla, Wadih; Forbes, Lisa R; Mace, Emily M; Cao, Tram N; Coban-Akdemir, Zeynep H; Jhangiani, Shalini NImmunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responsesItem Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome(2018) Poli, Cecilia; Ebstein, Frédéric; Nicholas, Sarah K.; Guzman, Marietta M. de; Forbes, Lisa R.; Chinn, Ivan K.; Mace, Emily M.; Vogel, Tiphanie P.; Carisey, Alexandre F.; Benavides, Felipe; Coban-Akdemir, Zeynep H.; Gibbs, Richard A.; Jhangiani, Shalini N.; Muzny, Donna M.; Carvalho, Claudia M. B.; Schady, Deborah A.; Jain, Mahim; Rosenfeld, Jill A .; Emrick, Lisa; Lewis, Richard A.; Lee, Brendan; Undiagnosed Diseases Network members; Zieba, Barbara A.; Küry, Sébastien; Krüger, Elke; Lupski, James R.; Bostwick, Bret L.; Orange, Jordan S.The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.Item HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related auto-inflammatory disease(2021) Martinez, Caridad; Ebstein, Frédéric; Nicholas, Sarah K.; Guzman, Marietta De; Forbes, Lisa R.; Delmonte, Ottavia M.; Bosticardo, Marita; Castagnoli, Riccardo; Krance, Robert; Notarangelo, Luigi D.; Krüger, Elke; Orange, Jordan S.; Poli, CeciliaInborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe autoinflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and autoinflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.Item Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease(2019) Dorjbal, Batsukh; Stinson, Jeffrey R.; Ma, Chi A.; Weinreich, Michael A.; Miraghazadeh, Bahar; Hartberger, Julia M.; Frey-Jakobs, Stefanie; Weidinger, Stephan; Moebus, Lena; Franke, Andre; Schäffer, Alejandro; Bulashevska, Alla; Fuchs, Sebastian; Ehl, Stephan; Limaye, Sandhya; Arkwright, Peter D.; Briggs, Tracy A.; Langley, Claire; Bethune, Claire; Whyte, Andrew F; Alachkar, Hana; Nejentsev, Sergey; DiMaggio, Thomas; Nelson, Celeste G.; Stone, Kelly D.; Nason, Martha; Brittain, Erica H.; Oler, Andrew J.; Veltri, Daniel P.; Leahy, T Ronan; Conlon, Niall; Poli, Cecilia; Borzutzky, Arturo; Cohen, Jeffrey I.; Davis, Joie; Lambert, Michele P.; Romberg, Neil; Sullivan, Kathleen E.; Paris, Kenneth; Freeman, Alexandra F.; Lucas, Laura; Chandrakasan, Shanmuganathan; Savic, Sinisa; Hambleton, Sophie; Patel, Smita Y.; Jordan, Michael B.; Theos, Amy; Lebensburger, Jeffrey; Atkinson, Prescott; Torgerson, Troy R.; Chinn, Ivan K.; Milner, Joshua D.; Grimbacher, Bodo; Cook, Matthew C.; Snow, Andrew L.Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. Methods: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. Results: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. Conclusion: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.Item Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles(2018) Coban-Akdemir, Zeynep; White, Janson J.; Song, Xiaofei; Jhangiani, Shalini N.; Fatih, Jawid M.; Gambin, Tomasz; Bayram, Yavuz; Chinn, Ivan K.; Karaca, Ender; Punetha, Jaya; Poli, Cecilia; Baylor-Hopkins Center for Mendelian Genomics; Boerwinkle, Eric; Shaw, Chad A.; Orange, Jordan S.; Gibbs, Richard A.; Lappalainen, Tuuli; Lupski, James R.; Carvalho, Claudia M.B.Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.