JAGN1 (Jagunal-homolog1) is a ER-resident transmembrane protein which is part of the early secretory pathway and granulocyte colony-stimulating factor receptor mediated signaling. Autosomal recessively inherited variants in the JAGN1 gene lead to congenital neutropenia, early-onset bacterial infections, aphthosis and skin abscesses due to aberrant differentiation and maturation of neutrophils. In addition, bone metabolism disorders and a syndromic phenotype, including facial features, short stature and neurodevelopmental delay, have been reported in affected patients. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a treatment option for patients who respond poorly to therapy with colony-stimulating factors (GM-CSF, G-CSF) and those who suffer from complicated infections despite treatment. In a retrospective multicenter study by EBMT IEWP in close collaboration with ESID and the French Neutropenia registry, data from 32 patients with JAGN1 deficiency were collected to describe the natural course of the disease, perform a phenotype-genotype analysis and evaluate the responses to various treatment modalities. Patients presented with nine distinct homozygous mutations in JAGN1. All patients experienced early-onset infectious complications. Twelve patients presented a syndromic phenotype with short stature and facial features. Neurodevelopmental delay was observed only in four patients from three families. The most common variant c.3G>A p.Met1, found in nine patients in our cohort was never connected to extramedullary symptoms except for a short stature in one patient, whereas patients with the variants c.63G>T, p.Glu21Asp and c130c>T p.His44 Tyr presented more often with syndromic facial features and bone metabolism disorders. Six patients received allogeneic stem cell transplantation due to therapy-refractory neutropenia and severe infections, and one received the graft because of myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). Two patients had to undergo a second transplantation because of autologous reconstitution despite receiving myeloablative regimens. One untransplanted patient died at the age of five years due to pancolitis and septicemia. All 31 other patients were reported to be alive and healthy at the last follow-up under supportive care.
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