Autoimmune Cytopenia: Genetics and Pathophysiological Mechanism in Pediatric Evans Syndrome (ACTION)

Characterization of the genetic causes, and of the immunopathological clinical and biological manifestations in children with pediatric Evans syndrome included in a prospective national observational cohort of rare diseases.

Pediatric Evans syndrome (pES) is a rare and severe disease combining immunologic thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA). French patients from the 30 hematologic pediatric centers are from 2004 included in a prospective national OBS'CEREVANCE cohort. A first pilot study revealed a monogenic cause in 7/18 patients (40%) with mutations in the CTLA-4, LRBA, STAT3 GOF, and KRAS. TNGS or exome studies were performed between 2015 and 2018 inn 80 patients with pSE from the OBS'CEREVANCE cohort. This approach, combined with by immunophenotyping lymphocyte, identified a genetic cause of the disease in 26 patients (32%) (TNFRSF6, CTLA4, LRBA, STAT3 GOF, PIK3CD, RAG1, KRAS) and potential causal mutations in 18 other patients (22%), bringing the proportion of potential single gene cause to 76%. The central hypothesis of this study is that most, if not all, cases of pSE are related to a monogenic or digenic cause, possibly with the intervention of genetic modifiers such as somatic mutations.

Collection of biological samples of children with pSE included in the the OBS'CEREVANCE cohort and their parents, for genetic and functional immunological analyzes.

A first systematic approach by Targeted-Next Generation Sequencing will be used on the entire cohort of patients with pSE. This step will be performed on a sequencing chip specifically developed to detect anomalies in known genes involved in autoimmunity. In patients for whom no mutations are identified, a whole exome sequencing (WES) approach will be applied to patients and their parents to seek to identify mutations in new genes that may be related to pSE. In patients for whom this WES approach is unsuccessful, the search for somatic lymphocyte mutations, or copy number variants will be performed before considering a complete genome sequencing . If several candidate genes are identified, the clinical data provided by the CEREVANCE and the phenotypic analyses carried out prior to genetic analyses by the CEDI laboratory will guide the choices to prioritize the study of the identified variants.

The number of biological samples collected for PSE children included in the OBS'CEREVANCE cohort and their relatives will be recorded

Inclusion Criteria: Patient registered in the French national prospective OBS'CEREVANCE cohort Diagnosis of pediatric Evans syndrome (PTI+AHAI) Age strictly under 18 years at the initial onset Child residing in metropolitan France and affiliated to a french health insurance system Free, informed, written and signed consent Exclusion Criteria: Evans syndrome secondary to chemotherapy, bone marrow transplantation or organ transplantation. Refusal to participate from parents/patients