Submission Details

MCM10 was first reported in relation to immunodeficiency 80 with or without congenital cardiomyopathy (MONDO: 0016587) by Mace et al in 2020 (PMID: 32865517). Inheritance in all reported cases is compound heterozygous. This condition is characterized by early onset disease profound NK cell deficiency with impaired maturation, T and B cell lymphopenia and disseminated cytomegalovirus infection, as well as antenatal restrictive cardiomyopathy with thymic and splenic hypoplasia. Evidence supporting this gene-disease relationship includes case-level and experimental data. Of the 4 reported cases, the first presented age 16 months and succumbed to overwhelming CMV age 24 months, with compound heterozygous mutations (non-sense and missense) (PMID: 32865517). The remaining 3 were sibling identified antenatally all experienced perinatal mortality with compound heterozygous mutations (non-sense and cryptic splice acceptor) (PMID: 3371261). Both parents of each proband were healthy heterozygotes for a single variant, suggesting necessity of biallelic variants to cause disease.

This gene-disease relationship is supported by biochemical function, expression studies, functional assays, a cell culture and a mouse model (PMIDs:15494305, 25613900, 33712616, 32865517). In healthy subjects, MCM10 is a conserved component of the eukaryotic replisome, and promotes initiation of DNA replication through interactions with CDC45, MCM2-7 and GINS (CMG) complex. After origin firing it controls fork stability to support elongation through recruitment of DNA POL alpha-1 and PCNA and stabilizes the replisome to prevent replication stress and promote gene stability (PMID: 28218679). In budding yeast expressing tagged MCM10, Ricke et al demonstrated that MCM10 remains at replication origins until activated but is displaced only after firing (PMID: 15494305), supporting its role in DNA replication. MCM10 is highly expressed in bone marrow and lymphoid tissues (PMID: 25613900). Transformed primary patient-derived fibroblasts showed aberrant cell cycle dynamics, whilst patient fibroblasts harbor increased DNA damage, nuclear area and proportions of S phase cells, suggesting cell cycle defects and replication stress (PMID 32865517). Late passage HCT116 MCM10+/- showed genomic instability, chromosomal rearrangements at common fragile sites and shorter early passage telomeres with erosion overtime (PMID: 33712616). A CD34+ hematopoietic stem cell MCM10KD model demonstrated an NK cell maturation defect similar to the stage 4 arrest seen in the Mace proband (PMID: 32865517). Finally, a murine model reconstituted with primary patient fibroblasts reprogramed to generate iPS, demonstrated enrichment of CD56bright NK cell subset in peripheral blood and spleen with evidence of DNA damage compared to healthy controls, again recapitulating the NK cell maturation arrest seen in Mace proband (PMID: 32865517).

In summary, there is moderate evidence to support this gene-disease relationship. Whilst more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date June 20th 2024 (SOP Version 9).