Location matters: topography of germline CEBPA variants predicts variable outcomes in familial acute myeloid leukaemia—a rare disease perspective

Background Familial acute myeloid leukaemia (AML) with germline CEBPA (CCAAT/enhancer-binding protein alpha) variants is a distinct hereditary entity, yet clinically meaningful genotype–phenotype correlations remain incompletely defined. Methods We integrated cases from our institution with all published pedigrees of germline CEBPA -mutated AML and analysed 56 affected patients from 40 families, including one newly identified pedigree harbouring a novel TAD2 (transactivation domain 2) variant (p.C133Ter). Results Variant localisation significantly influenced disease phenotype and outcome. Compared with non-TAD2 variants, TAD2 variants were associated with older age at AML onset (40 years vs 21 years, p<0.001), a higher burden of cooperating somatic variants (64.3% vs 27.3%, p=0.023) and lower complete remission rates after induction therapy (69.2% vs 95.3%, p=0.022). TAD2 involvement conferred inferior overall survival (p<0.001) and progression-free survival (p=0.025). In univariate analyses, TAD2 variants emerged as adverse prognostic factors for 2-year overall survival (OR=0.06, 95% CI 0.01 to 0.34, p=0.002) and progression-free survival (OR=0.07, 95% CI 0.01 to 0.35, p=0.003). Conclusions Although germline CEBPA -mutated AML is generally regarded as favourable-risk, TAD2-involving variants may define a biologically and clinically high-risk subset, supporting variant topography as a clinically actionable prognostic marker.