Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

Familial platelet disorder with predisposition to acute myelogenous leukaem ia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop a cute myelogenous leukaemia (AML). Informative recombination events in 6 FPD /AML pedigrees with evidence of linkage to markers on chromosome 21q identi fied an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AM L1) that co-segregated with the disease in four FPD/AML pedigrees. We ident ified heterozygous CBFA2 missense mutations that co-segregated with the dis ease in the remaining two FPD/AML pedigrees at phylogenetically conserved a mino acids R166 and R201, respectively. Analysis of bone marrow or peripher al blood cells from affected FPD/AML individuals showed a decrement in mega karyocyte colony formation, demonstrating that CBFA2 dosage affects megakar yopoiesis. Our findings support a model for FPD/AML in which haploinsuffici ency of CBFA2 causes an autosomal dominant congenital platelet defect and p redisposes to the acquisition of additional mutations that cause leukaemia.