{"id":16461,"date":"2025-08-27T10:54:29","date_gmt":"2025-08-27T13:54:29","guid":{"rendered":"https:\/\/www.ufrgs.br\/ppgbm\/?p=16461"},"modified":"2025-08-27T10:54:29","modified_gmt":"2025-08-27T13:54:29","slug":"27-08-seminario-de-dados-mestrado-leonardo-martinello-da-rosa","status":"publish","type":"post","link":"https:\/\/www.ufrgs.br\/ppgbm\/27-08-seminario-de-dados-mestrado-leonardo-martinello-da-rosa\/","title":{"rendered":"27\/08 – SEMIN\u00c1RIO DE DADOS (Mestrado) – LEONARDO MARTINELLO DA ROSA"},"content":{"rendered":"

SEMIN\u00c1RIOS DE DADOS (Mestrado) <\/strong><\/p>\n

\u00a0<\/strong><\/p>\n

LEONARDO MARTINELLO DA ROSA<\/strong><\/p>\n

Doen\u00e7a Granulomatosa Cr\u00f4nica: an\u00e1lise cl\u00ednica e gen\u00e9tica de uma coorte de pacientes do Sul do Brasil (Chronic Granulomatous Disease: clinical and genetic analysis of a cohort of patients from Southern Brazil)<\/strong><\/p>\n

Orientadora: Dra. Fernanda Sperb Ludwig<\/p>\n

Coorientadora: Dra. Ida Vanessa Doederlein Schwartz<\/p>\n

Avaliador: Dr. Jos\u00e9 Artur Bogo Chies<\/p>\n

27 de agosto de 2025 (quarta-feira)<\/p>\n

Hor\u00e1rio de in\u00edcio: 12h<\/strong><\/p>\n

Presencial:\u00a0<\/strong>Anfiteatro do Departamento de Gen\u00e9tica da UFRGS (Campus do Vale, pr\u00e9dio 43312)<\/p>\n

 <\/p>\n

Resumo:<\/strong><\/p>\n

A Doen\u00e7a Granulomatosa Cr\u00f4nica (DGC) \u00e9 um erro inato da imunidade raro, causado por variantes patog\u00eanicas em genes que codificam os componentes do complexo NADPH oxidase, respons\u00e1vel por gerar esp\u00e9cies reativas de oxig\u00eanio (ROS) em fag\u00f3citos. A produ\u00e7\u00e3o deficiente de ROS predisp\u00f5e indiv\u00edduos com DGC a infec\u00e7\u00f5es recorrentes, complica\u00e7\u00f5es inflamat\u00f3rias, autoimunidade e malignidades. Este estudo teve como objetivo caracterizar uma coorte de pacientes com suspeita cl\u00ednica de DGC. Informa\u00e7\u00f5es cl\u00ednicas e bioqu\u00edmicas foram coletadas de prontu\u00e1rios de atendimento, e amostras de sangue perif\u00e9rico foram utilizadas para extra\u00e7\u00e3o do DNA gen\u00f4mico. O sequenciamento massivo paralelo foi realizado por meio de um painel para genes associados \u00e0 DGC (CYBB<\/em>, CYBA<\/em>, NCF1<\/em>, NCF2<\/em> e NCF4<\/em>) e tamb\u00e9m por sequenciamento de genoma completo. Para detectar uma dele\u00e7\u00e3o GT patog\u00eanica no gene NCF1<\/em> e distingui-lo de seus pseudogenes que naturalmente apresentam essa dele\u00e7\u00e3o, o m\u00e9todo gene-scan<\/em> foi utilizado conforme descrito por Dekker et al. (2001). A an\u00e1lise e classifica\u00e7\u00e3o das variantes seguiu as diretrizes da ACMG e ClinGen. Foi realizada um alinhamento m\u00faltiplo de gp91phox (CYBB<\/em>) entre 10 esp\u00e9cies, e uma modelagem tridimensional do complexo NADPH e an\u00e1lise estrutural de variantes. Seis pacientes do sexo masculino oriundos do Rio Grande do Sul foram analisados e geneticamente diagnosticados. Os \u00f3rg\u00e3os mais comumente afetados foram os pulm\u00f5es, pele e linfonodos; as manifesta\u00e7\u00f5es cl\u00ednicas mais comuns mais comuns inclu\u00edram casos de pneumonias recorrentes, envolvimento cut\u00e2neo, manifesta\u00e7\u00f5es em linfonodos e falha no desenvolvimento. Quatro pacientes apresentaram a DGC ligada ao X devido a variantes em CYBB<\/em>: duas variantes provavelmente patog\u00eanicas de troca de sentido, sendo uma delas in\u00e9dita, afetando um res\u00edduo de ciste\u00edna altamente conservado, causando danos tanto na estrutura da gp91phox quanto na intera\u00e7\u00e3o do complexo NADPH oxidase; e duas variantes patog\u00eanicas sem sentido, sendo uma predita para sofrer decaimento de mRNA mediado por c\u00f3don de parada prematuro, e a outra previamente observada em estudos funcionais com aus\u00eancia de express\u00e3o g\u00eanica. Dois pacientes que s\u00e3o irm\u00e3os foram diagnosticados com DGC autoss\u00f4mica recessiva causada pela dele\u00e7\u00e3o GT em NCF1<\/em>. Um deles \u00e9 heterozigoto para a dele\u00e7\u00e3o, sugerindo evento de recombina\u00e7\u00e3o na presen\u00e7a de um pseudogene sem a dele\u00e7\u00e3o GT, o que resultaria na aus\u00eancia de alelos funcionais. A DGC faz parte de um grupo de doen\u00e7as raras e subdiagnosticadas, destacando-se a relev\u00e2ncia de caracteriza\u00e7\u00e3o dos quadros cl\u00ednicos e do diagn\u00f3stico gen\u00e9tico preciso, que contribui com o manejo da doen\u00e7a, aconselhamento gen\u00e9tico, e transplante de medula \u00f3ssea.<\/p>\n

 <\/p>\n

Abstract:<\/strong><\/p>\n

Chronic Granulomatous Disease (CGD) is a rare inborn error of immunity caused by pathogenic variants in genes encoding the components of the NADPH oxidase complex, which is responsible for generating reactive oxygen species (ROS) in phagocytes. Deficient ROS production predisposes individuals with CGD to recurrent infections, inflammatory complications, autoimmunity, and malignancies. This study aimed to characterize a cohort of patients with clinical suspicion of CGD. Clinical and biochemical data were retrieved from medical records, and peripheral blood samples were used for genomic DNA extraction. Next-generation sequencing was performed using a targeted gene panel for CGD-associated genes (CYBB<\/em>, CYBA<\/em>, NCF1<\/em>, NCF2<\/em>, and NCF4<\/em>), as well as whole-genome sequencing. To detect the pathogenic GT deletion in NCF1<\/em> and distinguish it from its pseudogenes, which naturally harbor this deletion, the gene-scan method was applied as described by Dekker et al. (2001). Variant analysis and classification followed ACMG and ClinGen guidelines. Multiple sequence alignment of gp91phox (CYBB<\/em>) across 10 species was performed, along with three-dimensional modeling of the NADPH oxidase complex and structural variant analysis. Six male patients from Rio Grande do Sul, Brazil, were genetically diagnosed. The most commonly affected organs were the lungs, skin, and lymph nodes; the most frequent clinical manifestations included recurrent pneumonia, cutaneous involvement, lymph node manifestations, and failure to thrive. Four patients presented with X-linked CGD due to variants in CYBB<\/em>: two likely pathogenic missense variants, one of them novel, affecting a highly conserved cysteine residue and impairing both gp91phox structure and NADPH oxidase complex interactions; and two pathogenic nonsense variants, one predicted to undergo nonsense-mediated mRNA decay, and the other previously reported in functional studies showing absent gene expression. Two siblings were diagnosed with autosomal recessive CGD caused by the GT deletion in NCF1<\/em>. One of them was heterozygous for the deletion, suggesting a recombination event involving a pseudogene lacking the GT deletion, resulting in the absence of functional alleles. CGD belongs to a group of rare and underdiagnosed diseases, underscoring the relevance of clinical characterization and precise genetic diagnosis, which contribute to disease management, genetic counseling, and hematopoietic stem cell transplantation.<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

SEMIN\u00c1RIOS DE DADOS (Mestrado) \u00a0 LEONARDO MARTINELLO DA ROSA Doen\u00e7a Granulomatosa Cr\u00f4nica: an\u00e1lise cl\u00ednica e gen\u00e9tica de uma coorte de pacientes do Sul do Brasil (Chronic Granulomatous Disease: clinical and […]<\/p>\n","protected":false},"author":3,"featured_media":16462,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[108],"tags":[],"class_list":["post-16461","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-seminarios-e-defesas"],"_links":{"self":[{"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/posts\/16461","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/comments?post=16461"}],"version-history":[{"count":1,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/posts\/16461\/revisions"}],"predecessor-version":[{"id":16463,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/posts\/16461\/revisions\/16463"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/media\/16462"}],"wp:attachment":[{"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/media?parent=16461"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/categories?post=16461"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ufrgs.br\/ppgbm\/wp-json\/wp\/v2\/tags?post=16461"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}