Submission Details

NPM1 was first reported in relation to autosomal dominant bone marrow failure syndrome in 2019 (Nachmani et al., PMID: 31570891). Variants in NPM1 have been identified in individuals reported as having classic dyskeratosis congenita. However, due to the lack of association between NPM1 and telomere maintenance function, we determined that the syndrome described in Nachmani et al. is best described as bone marrow failure syndrome. As there are no other reported disease associations with NPM1 variants, no lumping and splitting was needed for this curation. Two variants (missense and an in-frame deletion) that have been reported in two probands in one publication (PMID:31570891) are included in this curation. These variants were observed in individuals with bone marrow failure with additional features including skin pigmentation abnormalities, nail dystrophy, thrombocytopenia, growth defects and skeletal abnormalities; telomere length was not reported. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, in vitro functional assays including cell line rescue and biochemical function evidence (PMID: 31570891). In summary, there is limited evidence supporting the relationship between NPM1 and autosomal dominant bone marrow failure syndrome. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date April 8, 2025 (SOP Version 11).