GINS4

Inheritance Pattern: AR

Disease ID:MONDO:0015131

Submitter: ClinGen

GINS4 was first reported in relation to autosomal recessive combined immunodeficiency due to GINS4 deficiency by Conte et al in 2022 (PMID: 36345943). This condition is characterized by neutropenia, viral and bacterial infections, and NK cell deficiency with impaired maturation. The T and B cell counts along with immunoglobulin levels were within normal ranges for all patients. Half of the patients presented with either dental abscesses or gingivitis. Evidence supporting this gene-disease relationship includes case-level and experimental data. Of the 5 reported cases, one individual presented at birth with intrauterine growth restriction, growth delay, tonsillar hypertrophy, cryptorchidism, and developed seizures with intracranial calcification, suggestive of CMV infection because these features were not reported present in any of the other probands. By 3 years of age the patient experienced multiple infections including varicella, recurrent otitis media, necrotizing nasolabial ulcers, gastrointestinal sepsis, and pneumonia. The patient and sister were compound heterozygous (missense and non-sense); however the sister had a milder case including varicella and recurrent herpes labialis, which was also observed mother (non-sense mutation carrier) (PMID: 36345943). Functional studies using cells derived from this original family demonstrated variable NK cell maturation across the affected siblings despite the same genotype, thus supporting the variable expressivity within this family (PMID:40768335). A single missense variant, p.V171M was found homozygous in three reportedly unrelated families from the same region of Africa, Comoros, suggesting this may be a founder mutation (PMID:340510848). Both parents of each proband were reportedly healthy heterozygotes for a single variant, suggesting necessity of biallelic variants to cause disease. However, those with LOF variants may exhibit mild features. This gene-disease relationship is supported by biochemical function, expression studies, functional assays, and protein interactions (PMIDs: 36345943, 40768335). Briefly, the GINS4 protein was demonstrated to be a part of the GINS complex which is important for DNA replication, specifically it acts as a helicase to unwind DNA. Other genes within this complex have been demonstrated to lead to NK cell abnormalities when disrupted (eg; GINS1 deficiency). Conte et al (2022) demonstrated that the alterations identified in the original family impacts GINS4 stability and the stability of other GINS complex proteins. Furthermore, they showed that these variants are associated with mild delays in cell cycle progression, but does not impact DNA replication fork speed and symmetry but does impair mitotic exit and entry into S phase. With regards to its role in NK cell maturation, the same group demonstrated that GINS4 is essential for NK cell differentiation through study of affected individuals cells (PMID: 36345943 and 40768335). 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 November 20th 2025 (SOP Version 11).