MCM4

Inheritance Pattern: AR

Disease ID:MONDO:0012383

Submitter: ClinGen

*MCM4* was first reported in relation to autosomal recessive inheritance of primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency in 2012 (Hughes et al., PMID: 22354170) and (Gineau et al., PMID: 22354167). This condition is characterized by adrenal failure, short stature, and natural killer (NK) cell deficiency. Affected individuals are also typically susceptible to recurrent infections. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The only identified variant (a hypomorphic splice site mutation) in this gene has been reported in 7 probands, segregating with disease in five families from the Irish Traveler community. (PMIDs: 22354170, 22354167, 22499342). This gene-disease relationship is supported by its biochemical function, expression studies, functional assays, rescue studies, and a mouse model (PMIDs: 22354170, 22354167, 10567526, 17143284). In healthy subjects, *MCM4* is part of a complex genetic machinery responsible for genome stability and correct DNA replication with a role in single strand DNA binding (PMID: 10567526). In FGD patients, the specific impact of MCM4 variants is not fully understood but in a functional assay supports the hypothesis that the lack of full length *MCM4* results in selective lack of CD56dim in NK cells (PMID: 22354167). The same author detected no full-length *MCM4* protein in patient 1.2 (P1.2) EBV-B cells as well as P1.3 and P2.1 primary and SV40 fibroblasts, by Western blotting (Gineau et al., PMID: 22354167). In addition, Hughes et al, completed another expression study using immunoblotting in which control subjects were observed to have two main protein species, of approximately 96 and 85 kDa, while predicted full-length 96-kDa product is missing in the patients (Hughes et al., PMID: 22354170). Gineau et al., also addressed the impact of the mutated *MCM4* allele on DNA replication itself by investigating the cell cycle and DNA content in SV40 fibroblasts and identified a rescue. WT *MCM4* or the patients’ *MCM4* allele were expressed in patient fibroblasts and authors assessed the breakage phenotype to demonstrate that the observed genomic instability was due to the absence of the full-length MCM4 in the patients’ cells. Expression of the WT allele greatly decreased the number of DNA breaks per metaphase, whereas expression of the mutant allele did not (PMID: 22354167). Lastly, a mouse model with a hypomorphic *MCM4* allele recapitulated the increased genomic instability observed in patients, though it lacked additional features of the disease (PMID: 17143284). 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.

Inheritance Pattern: AR

Disease ID:MONDO:0012383

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012383

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012383

Submitter: Labcorp Genetics (formerly Invitae)