Variation and impact of polygenic hematologic traits in monogenic sickle cell disease

Several of the complications observed in sickle cell disease (SCD) are influenced by variation in hematologic traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified thousands of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested whether these PTS associate with HT in SCD patients and if they can improve statistical models associated with SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD individuals of African ancestry. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these HT which are measured as part of routine practice were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (20.5-27.1%), associated with acute chest syndrome and stroke risk, and improved the statistical modeling of the vaso-occlusive crisis rate. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 39% (P=0.0006). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives

Description, évolution et génétique des atteintes neurologiques dans les cytopénies auto-immunes de l’enfant

Neurological involvement has been poorly described in autoimmune cytopenias (AIC) and association evokes an underlying primary immunodeficiency (PID). Among the 1,167 patients of the OBS’CEREVANCE nationwide prospective cohort which includes children with an AIC, we have identified 8 patients with a neurological involvement. Data were collected from all centers and radiological review was centralized. Genetic analyses were performed by a research department. With a median (range) follow-up of 12 years (6-26.5), 7 children had Evans Syndrome (ES) (with autoimmune neutropenia in 5) and 1 had autoimmune hemolytic anemia (AIHA). Neurological symptoms appeared were: seizures (n=4), cranial nerve palsy (n=2), Brown-Sequard syndrome (n=2) and/or sensory neuronopathy (n=1). No infectious pathogens were identified. MRI showed multiple (n=6) or unique (n=2) inflammatory lesions, histologically confirmed in 5 patients. In 4 cases, a lymphocytic meningitis was associated. Non-neurological organ involvement was present in all patients, mainly pulmonary nodules (n=6) and lymphoproliferation (n=4). All patients had a lymphocytes deficiency and 7 had a hypogammaglobulinemia. Patients have been given steroids (n=7), intravenous immunoglobulins (n=2) or immunosuppressive treatment (n=3), improving symptomatology and MRI for all. Five patients relapsed and 3 had an asymptomatic radiological progression. Four out of the 6 patients analyzed had a PID: 22q11.2 microdeletion (n=1), heterozygous CTLA4 mutation (n=2) or suspected homozygous LRBA mutation (n=1). In conclusion, neurological involvement is a rare and severe late event in childhood ES, or exceptionally AHAI, that may reveal various PID.Les atteintes neurologiques ont été peu décrites dans les cytopénies auto-immunes (CAI) et évoquent un déficit immunitaire primitif (DIP). Parmi les 1 167 enfants de la cohorte prospective française de CAI OBS’CEREVANCE, nous avons identifiés 8 patients avec une atteinte neurologique. Les données ont été récupérées auprès de chaque centre et les IRM relues de manière centralisée. Les analyses génétiques ont été effectuées par un laboratoire de recherche. Les patients ont en médiane (extrêmes) ont été suivis 12 (6-26,5) ans. Sept avaient un syndrome d’Evans (SE) et 1 une anémie hémolytique auto-immune (AHAI). L’atteinte neurologique consistait en : convulsions (n=4), paralysie des nerfs crâniens (n=2), syndrome de Brown-Séquard (n=2) et/ou ganglionopathie (n=1). Aucun pathogène n’a été identifié. Les IRM montraient des lésions inflammatoires multiples (n=6) ou unique (n=2), confirmées histologiquement chez 5 patients. Les patients présentaient également une méningite lymphocytaire (n=4), une lymphopénie (n=8) et/ou une hypogammaglobulinémie (n=7). Tous présentaient une atteinte d’organe non neurologique, principalement des nodules pulmonaires (n=6) et une lymphoprolifération (n=4). Les patients ont été traités par corticoïdes (n=7), immunoglobulines polyvalentes (n=2) ou immunosuppresseurs (n=3), améliorant chez tous la clinique et l’imagerie. Cinq patients ont rechuté et 3 ont montré une progression radiologique asymptomatique. Quatre des 6 patients analysés avaient un DIP : microdéletion 22q11.2 (n=1), mutation hétérozygote de CTLA4 (n=2) ou mutation homozygote suspectée de LRBA (n=1). Cette association rare et sévère concerne surtout les SE et peut révéler un DIP

Long-term follow-up of subtotal splenectomy for hereditary spherocytosis: a single-center study

International audienc

Subtotal and total splenectomy for hereditary pyropoikilocytosis: Benefits and outcomes

International audienc