Tracking Cytopenias in FANCA-deficient Fanconi Anemia

Fanconi anemia (FA) is an inherited disorder classically characterized by childhood-onset bone marrow dysfunction and lifelong cancer predisposition. FA is caused by pathogenic variants in any one of 23 genes identified so far. Of these, FANCA is the most frequently mutated and accounts for disease in two-thirds of all patients with FA. The spectrum of FANCA pathogenic variants (mutations) is broad, and genotype-phenotype correlation is often unclear. Here we describe the natural history of cytopenias associated with FANCA pathogenic variants in 139 individuals diagnosed in 1995 or later. We followed blood cell counts over time and correlated these with the classification of patient mutation subtypes. Most participants experienced age-related declines in hematologic parameters beginning in early childhood. Platelets underwent the earliest decline, reaching platelet count below 50K/l at a median age of 8.2 years. The erythrocyte lineage was the most stable with hemoglobin below 8 g/dl identified at a median age of 10.7 years. Androgen therapy delayed the blood count decline. The presence of at least one predicted hypomorphic pathogenic variant in the FANCA gene significantly slowed the progression of the hematologic abnormalities. This study sheds light on the importance of mutation type in predicting the severity of hematological manifestations in FA. Furthermore, it serves as a historical comparative cohort for emerging therapies aimed at altering hematological disease progression in FANCA-deficient FA patients. Key PointsO_LIThrombocytopenia and neutropenia are the earliest and most reliable indicators of hematologic decline in FANCA-deficient patients C_LIO_LIPresence of two FANCA variants with predicted complete loss of function leads to earlier onset and faster progression of disease C_LI