GINS1

Inheritance Pattern: AR

Disease ID:MONDO:0044725

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044725

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0044725

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044725

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044725

Submitter: ClinGen

*GINS1* (also known as *PSF1*), along with *GINS2-4*, belongs to the Go-Ichi-Ni-San (GINS) complex. The GINS complex is required for initiation and elongation of DNA replication by unwinding DNA and binding to single-stranded DNA. Overall, 5 patients with unaffected carrier parents from 4 unrelated families were found to be compound heterozygous for 4 rare variants, including two missense (p.R83C and p.C152Y) and two 5′ UTR nucleotide substitutions (c.–48C>G and c.–60A>G). These individuals show pre- and post-natal growth restriction, susceptibility to viral infections thought to be caused by NK cell deficiency, low or normal numbers of circulating T and B lymphocytes, and chronic neutropenia without adrenal insufficiency (PMID: 28414293). This gene-disease relationship is supported by biochemical function, expression studies, functional studies, a zebrafish model, and a mouse model. Cottineau et al further investigated the role that *GINS1* plays in NK deficiency. GINS1 patients had low proportions of both CD56bright and CD56dim subsets, which did not respond to stimulation with IL-2 or IL-15. Cells from patients had lower *GINS1* protein levels than control, suggesting that both 5′ UTR and missense mutations affected protein levels. *GINS3 *and *GINS4* protein expression levels are also decreased in patient derived cells, indicating that GINS complex stability and function are affected by loss of *GINS1* protein expression. Additionally, fibroblasts from patients exhibited abnormal nuclear morphology, indicating a failure to maintain genome integrity and signify mis-segregation of chromosomes. DNA fiber analysis determined that patient cells had a decreased amount of replication clusters and bidirectional forks as well as an increase in stalled replication forks. Patient fibroblasts proliferate slower than controls and have a senescent phenotype. It is likely that these phenotypes contribute to natural killer deficiency, although the basis for neutropenia found in *GINS1* is not understood. There is evidence that in zebrafish, the absence of GINS function causes DNA replication to be cell impaired. Also, *gins1* mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (PMID: 32548116). Mice homozygous for a nonfunctional mutant of *PSF1* died in utero. *PSF1-/-* blastocysts failed to show outgrowth in culture and exhibited a cell proliferation defect (PMID: 16287864). Possibly explaining the lack of homozygous human patients studied. 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.