biostudies-literatureSeo SNational Institute of Allergy and Infectious DiseasesNIAID NIH HHS116102https://www.ebi.ac.uk/biostudies/studies/S-EPMC12450099biostudies-literatureUnknown44(8)While monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins cause human natural killer cell deficiencies (NKDs), family members with the same inherited variants often have variable clinical and cellular phenotypes. We investigated two siblings with inherited compound heterozygous GINS4 variants but variable disease expressivity. Cell cycle impairment and increased apoptosis were detected following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated expected biallelic expression of GINS4 in pluripotent cells and progenitors. However, Cell reportsAllelic bias contributes to heterogeneous phenotypes of NK cell deficiency.PMC12450099R01 AI189818R01 AI137275Seo SPatel AHegewisch-Solloa EMace EMPatil SLAhn YOSaturne MDBorowiak MCorneo BArmetta JGuilz NCfalseAllelic bias contributes to heterogeneous phenotypes of NK cell deficiency.While monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins cause human natural killer cell deficiencies (NKDs), family members with the same inherited variants often have variable clinical and cellular phenotypes. We investigated two siblings with inherited compound heterozygous GINS4 variants but variable disease expressivity. Cell cycle impairment and increased apoptosis were detected following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated expected biallelic expression of GINS4 in pluripotent cells and progenitors. However, 2025-01-01T00:00:00Z2025 Aug2026-06-03T15:34:09.409Z2026-06-01T03:06:28.782ZS-EPMC124500994076833510.1016/j.celrep.2025.116102