Person: Poli Harlowe, María Cecilia
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Poli Harlowe
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María Cecilia
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María Cecilia Poli Harlowe
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Publication Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile(2024) Poli Harlowe, María Cecilia; Rebolledo Jaramillo, Boris; Lagos, Catalina; Orellana, Joan; Moreno, Gabriela; Martín, Luz M.; Encina, Gonzalo; Böhme, Daniela; Faundes, Víctor; Zavala, M. Jesús; Hasbún, María Trinidad; Fischer, Sara; Brito, Florencia; Araya, Diego; Lira, Manuel; Cruz, Javiera de la; Astudillo, Camila; Lay-Son, Guillermo; Cares, Carolina; Aracena, Mariana; San Martín, Esteban; Coban-Akdemir, Zeynep; Posey, Jennifer E.; Lupski, James R.; Repetto, GabrielaRare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.Publication A Third Dose of SARS-CoV-2 mRNA Vaccine Improves Immune Response in Chronic Kidney Disease Patients(2023) Poli Harlowe, María Cecilia; Vial Cox, María Cecilia; Rey, Emma; González, Natalia; Cortés, Lina; Hormazabal, Juan; Ramírez, Carolina; De la Cruz, Javiera; Ulloa, CamiloChronic kidney disease (CKD) patients have an increased risk of morbidity and mortality following SARS-CoV-2 infection. Vaccination in these patients is prioritized, and monitoring of the immune response is paramount to define further vaccination strategies. This prospective study included a cohort of 100 adult CKD patients: 48 with kidney transplant (KT) and 52 on hemodialysis without prior COVID-19. The patients were assessed for humoral and cellular immune responses after four months of an anti-SARS-CoV-2 primary two-dose vaccination scheme (CoronaVac or BNT162b2) and one month after a booster third dose of BNT162b2 vaccine. We identified poor cellular and humoral immune responses in the CKD patients after a primary vaccination scheme, and these responses were improved by a booster. Robust polyfunctional CD4+ T cell responses were observed in the KT patients after a booster, and this could be attributed to a higher proportion of the patients having been vaccinated with homologous BNT162b2 schemes. However, even after the booster, the KT patients exhibited lower neutralizing antibodies, attributable to specific immunosuppressive treatments. Four patients suffered severe COVID-19 despite three-dose vaccination, and all had low polyfunctional T-cell responses, underscoring the importance of this functional subset in viral protection. In conclusion, a booster dose of SARS-CoV-2 mRNA vaccine in CKD patients improves the impaired humoral and cellular immune responses observed after a primary vaccination scheme.Publication Proteasome disorders and inborn errors of immunity(2023) Poli Harlowe, María CeciliaInborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.Publication The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS(2022) Gedik, Kader; Lamot, Lovro; Romano, Micol; Demirkaya, Erkan; Piskin, David; Torreggiani, Sofia; Adang, Laura; Armangue, Thais; Barchus, Kathe; Cordova, Devon; Crow, Yanick; Dale, Russell; Durrant, Karen; Eleftheriou, Despina; Fazz, Elisa; Gattorno, Marco; Gavazzi, Francesco; Hanson, Eric; Lee-Kirsch, Min Ae; Montealegre, Gina; Neven, Bénédicte; Orcesi, Simona; Ozen, Seza; Poli Harlowe, María Cecilia; Schumacher, Elliot; Tonduti, Davide; Uss, Katsiaryna; Aletaha, Daniel; Feldman, Brian; Vanderver, Adeline; Brogan, Paul; Goldbach, RaphaelaObjective: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. Methods: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. Results: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. Conclusion: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.