Submission Details

MDM4 was first reported in relation to autosomal dominant bone marrow syndrome 6 in 2020 (Toufektchan et al., 2020 PMID: 32300648). Patients present with bone marrow hypocellularity, neutropenia, and other variable features such as gastrointestinal symptoms, B cell deficiency, cytopenia/aplastic anemia, atrial septal defect, premature birth, and head and neck squamous cell carcinoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: bone marrow failure syndrome 6 (OMIM:618849), dyskeratosis congenita-like syndrome, and acute myeloid leukaemia/myelodysplastic syndrome.

Four variants (3 missense, 1 canonical splice site) that have been reported in four probands in 3 publications and 1 ClinVar submitter (PMIDs: 29146883, 32098966, 32300648, SCV002058868.1) are included in this curation. The mechanism of pathogenicity is reported to be loss of function which results in p53 increased activity (PMID: 32300648). This gene-disease relationship is also supported by experimental evidence. The c.1361C>T (p.Thr454Met) mutant RING domain had fully retained its capacity to bind ATP specifically but exhibited an altered capacity to interact with the MDM2 RING domain in a yeast two-hybrid assay (PMID: 32300648). Additionally, transfection of this mutation into human U2OS cells resulted in decreased levels of the mutant protein and lack of inhibition of TP53 (PMID: 32300648). In addition, a Mdm4T454M/T454M MEF cell culture model showed increased p53 activity and short telomeres (PMID: 32300648 ). The Mdm4+/T454M p53+/Δ31 mouse model exhibited bone marrow hypocellularity in the sternum sections of the moribund animals, intense skin hyperpigmentation, heart hypertrophy, thymic hypoplasia, and were much smaller than their littermates (PMID: 32300648). An additional mouse model revealed that Mdm4 is required for generating high erythropoietic rates during definitive fetal erythropoiesis (PMID: 17105817). Lastly, biochemical function studies demonstrated that Mdm4 and Mdm2 cooperate to inhibit p53 activity in vivo (PMID: 16492744).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 12/10/2024 (SOP Version 11).