Combined Immunodeficiency Due to GINS1 Deficiency — Comprehensive Disease Characteristics Report

Summary

Combined immunodeficiency due to GINS1 deficiency (MONDO:0044725; OMIM #617827, "Immunodeficiency 55" / IMD55) is an ultrarare, autosomal-recessive inborn error of DNA replication. It is caused by biallelic hypomorphic (partial loss-of-function) variants in GINS1 (also called PSF1), located at chromosome 20p11.21. GINS1 encodes one of four subunits (GINS1/PSF1, GINS2/PSF2, GINS3/PSF3, GINS4/SLD5) of the GINS complex, an essential component of the CDC45–MCM2-7–GINS (CMG) replicative helicase that unwinds double-stranded DNA at the eukaryotic replication fork. Because complete loss of GINS function is embryonic-lethal, all viable human disease results from partial deficiency, with residual GINS1 activity measured at roughly 3–16% in patient cells.

The disorder was first defined by Cottineau and colleagues in 2017, who described 5 patients from 4 kindreds and established the core clinical triad: intrauterine (and usually postnatal) growth retardation, chronic neutropenia, and NK-cell deficiency. Mechanistically, hypomorphic GINS1 impairs GINS complex assembly, producing basal replication stress, defective checkpoint signaling, impaired cell-cycle control, and genomic instability — all of which are rescued by wild-type GINS1. These defects selectively cripple highly proliferative cell compartments (fetal tissues driving growth; bone-marrow myeloid and NK-cell precursors), explaining the phenotype. Residual enzymatic activity correlates with the severity of growth retardation and the cellular phenotype, though the immunological phenotype is relatively uniform across genotypes.

A 2026 case report (Mackley et al.) expanded the phenotype, describing distinctive facial dysmorphism and glaucoma in addition to the core triad, and noted glaucoma appearing across multiple unrelated individuals — pointing toward genuine phenotypic expansion. To date only ~9–10 patients have been reported worldwide. GINS1 deficiency belongs to a small but coherent family of "replicative-helicase NK-cell deficiencies," most notably the closely analogous partial MCM4 deficiency (growth retardation, adrenal insufficiency, and selective NK deficiency) and the recently described CDC45 deficiency. Management is currently supportive; no curative, disease-specific therapy has been established, although hematopoietic stem cell transplantation is the conceptual analog drawn from other combined immunodeficiencies.

Key Findings

Finding 1 — GINS1 deficiency is an autosomal-recessive combined immunodeficiency defined by a core triad

Cottineau et al. (2017, J Clin Invest) studied 5 patients from 4 kindreds, all carrying compound-heterozygous rare mutations in GINS1 (PSF1). Every patient displayed intrauterine growth retardation, chronic neutropenia, and NK-cell deficiency, and 4 of 5 also had postnatal growth retardation. This paper established both the disease entity and its defining clinical signature.

"We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation." — PMID: 28414293

The inheritance and causal chain were summarized directly:

"Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency." — PMID: 28414293

A central genotype–phenotype relationship was that residual GINS1 activity graded with disease severity:

"The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype." — PMID: 28414293

Gene/identifier annotations: GINS1/PSF1, HGNC:28980, OMIM gene 610608, chromosome 20p11.21 (Ensembl ENSG00000101003; UniProt Q14691); disease OMIM #617827 (IMD55). Evidence type:* human clinical.

Finding 2 — Mechanism: GINS1 is an essential CMG replicative-helicase subunit; deficiency causes replication stress and genomic instability

The GINS complex is a 1:1:1:1 heterotetramer (SLD5/GINS4, PSF1/GINS1, PSF2/GINS2, PSF3/GINS3) essential for the initiation and progression of eukaryotic DNA replication. Together with CDC45 and the MCM2-7 hexamer it forms the CMG helicase, the molecular motor that separates the two DNA strands at the replication fork.

"The CMG [Cdc45-Mcm2-7-GINS(Psf1-3, Sld5)] helicase unwinds the double helix to separate the leading and lagging DNA strands." — PMID: 35038632

Complete loss is incompatible with life, underscoring the essentiality of the complex:

"The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice." — PMID: 28414293

Patient-derived fibroblasts provided direct cellular evidence for the pathomechanism, and crucially the defect was reversible with wild-type gene restoration:

"The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1." — PMID: 28414293

Evidence type: human clinical + in vitro (patient fibroblasts) + model organism (mouse lethality).

Finding 3 — Phenotypic spectrum expansion: dysmorphism, glaucoma, and variable infection burden

Mackley et al. (2026) reported a 2-year-old female with growth retardation, chronic neutropenia, distinctive facial features, and glaucoma, carrying compound-heterozygous likely-pathogenic variants c.-48C>G (p.?) and c.247C>T (p.Arg83Cys). Their review of all nine individuals reported to date reaffirmed the core triad while highlighting emerging features.

"We present a 2-year-old female with growth retardation, chronic neutropenia, distinctive facial features, and glaucoma. Exome sequencing revealed two likely pathogenic variants in GINS1, c.-48C>G p.? and c.247C>T p.Arg83Cys." — PMID: 41689265

"cementing growth retardation, neutropenia, and natural killer cell deficiency as core features." — PMID: 41689265

"glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion." — PMID: 41689265

Notably, this proband had no history of infections, illustrating that the infection burden is variable and that immunodeficiency may be "mildly symptomatic" in some patients. Evidence type: human clinical (case report + literature review).

Finding 4 — Model organisms and related helicasopathies contextualize the disease

Multiple orthogonal models support the mechanism and place GINS1 deficiency within a disease group:

• Mouse: Targeted disruption of Sld5 (GINS4) causes an inner-cell-mass proliferation defect and peri-implantation embryonic lethality, phenocopying Psf1 (GINS1)-null mice. Psf1 haploinsufficiency impairs acute proliferation of bone-marrow hematopoietic stem cells during 5-FU-induced regeneration.

"targeted disruption of SLD5 in mice causes a defect in cell proliferation in the inner cell mass, resulting in embryonic lethality at the peri-implantation stage." — PMID: 24244394

"haploinsufficiency of PSF1 resulted in failure of acute proliferation of bone marrow hematopoietic stem cells (HSCs) during reconstitution of bone marrow ablated by 5-FU treatment." — PMID: 24244394

• Drosophila: Knockdown of any of the four GINS genes (Sld5, Psf1, Psf2, Psf3) yields virtually identical mitotic phenotypes — chromosome condensation defects, chromosome breakage, and polyploidy — confirming the shared essential function of the complex (PMID: 40577589, PMID: 20709026).

• Analogous human helicasopathy (MCM4): Partial MCM4 deficiency causes a strikingly parallel human syndrome of growth retardation, adrenal insufficiency, and selective NK-cell deficiency with genomic instability — the key differential diagnosis.

"partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency." — PMID: 22354167

Together with reviews of inborn NK-cell errors (PMID: 24135998), these establish "replicative-helicase NK deficiencies" as a recognized category. Evidence type: model organism + human clinical (comparative).

Finding 5 — Genetic architecture: biallelic hypomorphic variants; heterozygotes unaffected; recurrent p.Arg83Cys

gnomAD v4 constraint metrics for GINS1 (ENSG00000101003) show pLI ≈ 2.5×10⁻⁷ (i.e., ~0) and observed/expected LoF (oe_lof) = 0.74 (90% CI 0.55–1.03). This indicates GINS1 is not loss-of-function-intolerant at the heterozygous level, fully consistent with a recessive disease in which carriers are healthy. Reported disease alleles span 5′UTR/promoter-proximal, missense, and splice classes. The Mackley 2026 case carried:

Of ~188 ClinVar GINS1 entries, the majority are variants of uncertain significance (VUS). The preserved residual activity (3–16%) confirms these are hypomorphic rather than null alleles.

"The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype." — PMID: 28414293

"Exome sequencing revealed two likely pathogenic variants in GINS1, c.-48C>G p.? and c.247C>T p.Arg83Cys." — PMID: 41689265

Evidence type: human clinical + computational (population genetics).

Finding 6 — Disease nosology and identifiers

Synonyms: CID due to GINS1 deficiency; IMD55; combined immunodeficiency with intrauterine growth retardation–NK cell deficiency–neutropenia; PSF1 deficiency. Information is derived from aggregated disease-level resources and individual patient case series (not EHR-scale data).

Finding 7 — GINS1/PSF1 protein biology and structure

UniProt Q14691 (GINS1/PSF1) is a 196-amino-acid nuclear DNA-replication factor localizing to the nucleus and chromosome. It is required for GINS complex function in the initiation and progression of DNA replication; GINS is a core component of the CMG helicase that unwinds template DNA. GINS1 forms a stable subcomplex with GINS4 (SLD5) and assembles the GINS heterotetramer (GINS1/2/3/4). Domain annotations: Pfam PF05916 (SLD5/GINS), InterPro IPR056783. Multiple experimental structures exist — the human GINS complex (PDB 2E9X, 2EHO, 2Q9Q) and cryo-EM human CMG replisome assemblies (PDB 6XTX, 6XTY, 7PFO, 8OK2, 9E2Z). Variant-induced failure of assembly directly links protein dysfunction to the cellular phenotype.

"The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability." — PMID: 28414293

Finding 8 — Clinical course, diagnostics, prognosis, and management

Cottineau (2017) established that the combined neutropenia + NK-cell deficiency arises from a maturation blockade in the bone marrow and was "mildly symptomatic." Onset is congenital/prenatal (IUGR), with a chronic postnatal course; growth-retardation severity tracks residual GINS1 activity.

"The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic." — PMID: 28414293

"The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation." — PMID: 28414293

Diagnostic workup: complete blood count (chronic neutropenia; HP:0001875); lymphocyte immunophenotyping showing reduced/absent NK cells (CD3⁻CD56⁺; NK deficiency HP:0040218) with relatively preserved T/B lymphocytes; NK cytotoxicity assays; bone-marrow examination (myeloid maturation arrest); growth assessment (IUGR/short stature HP:0001511/HP:0004322); and cytogenetic/genomic-instability testing. Molecular diagnosis is via WES/WGS or targeted inborn-errors-of-immunity/bone-marrow-failure gene panels including GINS1, with single-gene/segregation testing confirming biallelic variants. Evidence type: human clinical.

Section-by-Section Report

1. Disease Information

GINS1 deficiency is an ultrarare autosomal-recessive combined immunodeficiency and inborn error of DNA replication. Overview: biallelic hypomorphic variants in GINS1 partially impair the CMG replicative helicase, causing replication stress and a characteristic triad of growth retardation, chronic neutropenia, and NK-cell deficiency. Identifiers: MONDO:0044725; OMIM #617827 (IMD55); OMIM gene 610608; HGNC:28980; NCBI Gene 9837; Ensembl ENSG00000101003; UniProt Q14691; Orphanet "Combined immunodeficiency due to GINS1 deficiency"; no dedicated ICD-11/MeSH term (indexed under primary/severe combined immunodeficiency). Synonyms: IMD55, CID due to GINS1 deficiency, PSF1 deficiency, combined immunodeficiency with IUGR–NK deficiency–neutropenia. Source:* disease-level aggregation + individual case series (not EHR).

2. Etiology

Causal factor: monogenic — biallelic (compound heterozygous or homozygous) hypomorphic variants in GINS1. Genetic risk: the disease requires two defective alleles; heterozygous carriers are unaffected (pLI ≈ 0). No environmental, infectious, or lifestyle cause; there are no established modifier genes, protective alleles, or gene–environment interactions. Consanguinity increases risk of recessive homozygosity, as with all AR disorders. Residual GINS1 activity (a genotype-dependent quantitative trait) is the principal severity determinant. PMID: 28414293

3. Phenotypes

Quality-of-life impact: growth failure and chronic immune surveillance dominate; infection burden is variable and sometimes absent. PMID: 28414293, PMID: 41689265

4. Genetic/Molecular Information

Causal gene: GINS1 (PSF1), 20p11.21. Variant classes: 5′UTR (c.-48C>G), missense (c.247C>T p.Arg83Cys; c.455G>A p.Cys152Tyr Likely pathogenic), and splice. Population frequency: disease alleles are rare-to-ultrarare (p.Arg83Cys AF ~6.6×10⁻⁴; c.-48C>G AF ~3.9×10⁻⁶). Origin: germline. Functional consequence: partial loss of function (hypomorphic) with 3–16% residual activity; not gain-of-function or dominant-negative. Modifier genes/epigenetics/chromosomal abnormalities: none established. PMID: 28414293, PMID: 41689265

5. Environmental Information

No environmental, lifestyle, or infectious cause. Infections are downstream consequences of immunodeficiency, not triggers. Not applicable for toxin/occupational/dietary factors.

6. Mechanism / Pathophysiology

See the Mechanistic Model below. Molecular pathway: DNA replication initiation/elongation via the CMG helicase (GO:0006270, GO:0006260). Cellular processes: replication stress, S-phase/replication checkpoint signaling (GO:0000076), cell-cycle dysregulation, genomic instability. Protein dysfunction: impaired GINS heterotetramer assembly → destabilized CMG. Immune involvement: immunodeficiency via failed proliferation of NK-lineage and myeloid precursors (bone-marrow maturation blockade). Tissue-damage mechanism: proliferation failure/genomic instability in high-turnover compartments. PMID: 28414293, PMID: 35038632

7. Anatomical Structures Affected

Organ/system: bone marrow (UBERON:0002371) and immune system (primary); whole-body growth; eye (UBERON:0000970, glaucoma). Cell types (CL): natural killer cell (CL:0000623), neutrophil (CL:0000775), hematopoietic stem/progenitor cell (CL:0000037), myeloid precursors; patient fibroblasts show the cellular defect in vitro. Subcellular (GO CC): nucleus (GO:0005634), chromosome (GO:0005694), CMG complex (GO:0071162), GINS complex (GO:0000811). Lateralization: systemic/bilateral (e.g., glaucoma may be bilateral).

8. Temporal Development

Onset: congenital/prenatal (IUGR). Course: chronic, lifelong; growth retardation and cytopenias persist. Progression: generally stable rather than rapidly progressive; severity set largely at birth by residual activity. No defined staging. Critical period: fetal/early-childhood growth window. PMID: 28414293

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: appears complete for the core triad in biallelic individuals; expressivity variable for growth severity and emerging features. Epidemiology: ultrarare — only ~9–10 reported patients worldwide; no formal prevalence/incidence estimate. Carrier state: healthy (pLI ≈ 0). Consanguinity relevant as for all AR disease. No confirmed founder effect, anticipation, mosaicism, or sex bias documented given the tiny cohort. PMID: 28414293, PMID: 41689265

10. Diagnostics

Laboratory: CBC (chronic neutropenia), lymphocyte immunophenotyping (reduced/absent CD3⁻CD56⁺ NK cells, preserved T/B), NK cytotoxicity assay, bone-marrow aspiration (myeloid maturation arrest), cytogenetic/genomic-instability testing (patient fibroblasts). Genetic testing: WES/WGS or targeted IEI/bone-marrow-failure panels including GINS1; single-gene/segregation confirmation of biallelic variants; functional residual-activity assay as a confirmatory research tool. Differential diagnosis: partial MCM4 deficiency (adds adrenal insufficiency), CDC45 deficiency, other congenital neutropenias and NK-deficiency syndromes. PMID: 28414293, PMID: 22354167

11. Outcome / Prognosis

Immunodeficiency is often "mildly symptomatic"; the bone-marrow blockade underlies the cytopenias. Growth-retardation severity is prognostically tied to residual GINS1 activity. Given documented genomic instability, a theoretical (unquantified) malignancy risk exists by analogy to MCM4. No survival/mortality statistics are available due to the tiny cohort. PMID: 28414293

12. Treatment

No disease-specific or curative therapy is established. Management is supportive: infection surveillance/prophylaxis, treatment of neutropenia-related infections, growth monitoring, and ophthalmologic care for glaucoma. Hematopoietic stem cell transplantation (NCIT:C15431) is the conceptual analog from other combined immunodeficiencies but would not correct the intrinsic non-hematopoietic growth defect; its role is undefined. No gene/cell/RNA therapy or clinical-trial data specific to GINS1.

13. Prevention

No primary prevention (monogenic, congenital). Secondary/tertiary: early diagnosis, infection prophylaxis, and surveillance for complications. Genetic counseling for recessive recurrence risk (25% in carrier couples); carrier and prenatal/preimplantation testing available once familial variants are known. No newborn-screening program targets GINS1 specifically (though NK/immune deficiencies may be flagged by TREC-based SCID screening in some cases).

14. Other Species / Natural Disease

No naturally occurring companion-animal or wildlife disease documented (OMIA has no GINS1 entry). Orthologs are highly conserved: mouse Gins1/Psf1 and Gins4/Sld5; Drosophila Psf1/Psf2/Psf3/Sld5; yeast GINS (Sld5, Psf1-3). Evolutionary conservation of the CMG mechanism is strong across eukaryotes and archaea. Not zoonotic. PMID: 24244394, PMID: 40577589

15. Model Organisms

Mouse: Psf1-null and Sld5-null are embryonic-lethal (peri-implantation); Psf1 haploinsufficiency impairs regenerative HSC proliferation — recapitulates the proliferation-dependence but not the viable hypomorphic human phenotype (a hypomorphic knock-in is lacking). Drosophila: RNAi/mutant of any GINS subunit reproduces genomic-instability/mitotic defects. In vitro: patient-derived fibroblasts recapitulate impaired GINS assembly, replication stress, and genomic instability, rescued by WT GINS1 — the best available disease-relevant model. Limitation: no model reproduces the full human triad simultaneously. PMID: 24244394, PMID: 20709026, PMID: 28414293

Mechanistic Model / Interpretation

The pathophysiology of GINS1 deficiency follows a clean causal chain from a housekeeping molecular defect to a tissue-selective clinical phenotype:

  Biallelic hypomorphic GINS1 variants (residual activity 3–16%)
      │
      ▼
  Impaired assembly of the GINS heterotetramer (GINS1/2/3/4)
      │
      ▼
  Destabilized CMG helicase (CDC45–MCM2-7–GINS)
      │
      ▼
  Reduced/ slowed replication-fork unwinding  →  basal REPLICATION STRESS
      │
      ▼
  Impaired S-phase checkpoint signaling + defective cell-cycle control
      │
      ▼
  GENOMIC INSTABILITY (chromosome breakage, ↑ single-stranded DNA)
      │
      ▼
  Proliferation failure — selectively in HIGHLY DIVIDING compartments
       ├── Fetal/postnatal growth → IUGR + short stature
       ├── Bone-marrow myeloid precursors → maturation blockade → NEUTROPENIA
       └── NK-cell lineage (proliferation-dependent) → NK-CELL DEFICIENCY
      │
      ▼
  Variable viral susceptibility; emerging: dysmorphism, glaucoma

Upstream vs downstream: The primary (upstream) lesion is a quantitative deficit of a structural replisome subunit. Everything downstream — replication stress, checkpoint failure, genomic instability, and cell-cycle arrest — is a generic consequence of a weakened replication machine. The tissue selectivity of the clinical phenotype is not explained by tissue-specific gene function (GINS1 is ubiquitous) but by differential proliferative demand: the cell populations that must divide fastest during fetal development and hematopoiesis are the most sensitive to a partially crippled replisome. This is the unifying principle of the "replicative-helicase disorders."

Why NK cells specifically? NK-cell development appears exquisitely proliferation-dependent, which is why selective NK deficiency is a shared signature of GINS1, MCM4, and CDC45 defects. The mouse data reinforce this: Psf1 haploinsufficiency specifically impairs acute HSC proliferation under regenerative stress, precisely the condition under which a marginal replisome is exposed.

Comparison of replicative-helicase NK deficiencies:

This comparison is diagnostically useful: the combination of neutropenia + NK deficiency without adrenal insufficiency favors GINS1, whereas adrenal failure + NK deficiency points to MCM4.

Evidence Base

The evidence base is internally consistent: the human genetic/clinical data (28414293, 41689265) are mechanistically explained by orthogonal model-organism and biochemical studies, and the phenotype is cross-validated by the analogous MCM4/CDC45 disorders.

Limitations and Knowledge Gaps

1. Extremely small sample size. The entire literature comprises ~9–10 patients from a handful of kindreds. All epidemiological, prognostic, and genotype–phenotype statements are correspondingly uncertain; no formal prevalence/incidence exists (Orphanet lists it among ultrarare immunodeficiencies without a stable point estimate).

2. No dedicated natural-history or outcome study. Long-term survival, malignancy risk (theoretically elevated given genomic instability, by analogy to MCM4), and adult outcomes are unknown. Life expectancy and mortality figures cannot be quantified.

3. No disease-specific treatment evidence. There are no clinical trials, no gene- or cell-therapy data specific to GINS1, and no FDA-approved therapy. HSCT is a conceptual analog from other CIDs but its role for GINS1 (given the non-hematopoietic growth phenotype it would not correct) is undefined.

4. Variant interpretation is immature. Most ClinVar GINS1 entries are VUS; the recurrent p.Arg83Cys allele has conflicting classifications and a relatively high population frequency (AF ~6.6×10⁻⁴), complicating pathogenicity calls. Functional assays (residual-activity measurement) are the current gold standard but are not widely available.

5. Emerging features are provisional. Glaucoma and facial dysmorphism are reported in a subset; their penetrance, mechanism, and true association require more cases.

6. No direct patient-derived omics. Transcriptomic, proteomic, metabolomic, or single-cell datasets specific to GINS1-deficient patients were not identified; mechanistic inference relies on fibroblast functional assays and model organisms.

7. No purpose-built animal model of the human disease. Null mice are embryonic-lethal; a hypomorphic knock-in recapitulating the human hypomorphic state has not been reported, limiting preclinical therapeutic testing.

Proposed Follow-up Experiments / Actions

1. Build an international patient registry. Pool the ~10 known cases and prospectively enroll new ones to define natural history, infection burden, malignancy incidence, and survival — the single highest-value action for this ultrarare disease.

2. Generate a hypomorphic GINS1 mouse (or zebrafish) knock-in reproducing 3–16% residual activity, to model the viable human phenotype (growth retardation, neutropenia, NK deficiency) and serve as a preclinical platform. Null models are uninformative because they are lethal.

3. Functional variant-classification pipeline. Develop a standardized cellular assay (GINS complex assembly + residual replication activity + genomic-instability readout) to reclassify the many GINS1 VUS, especially p.Arg83Cys, and correlate residual activity with clinical severity across more genotypes.

4. Single-cell profiling of patient bone marrow and NK-lineage cells to pinpoint the exact developmental stage of the maturation blockade and test the "proliferation-demand" hypothesis for lineage selectivity.

5. Systematic screening for glaucoma and dysmorphism in all diagnosed patients to establish penetrance and determine whether ophthalmologic surveillance should be standard of care.

6. Assess long-term cancer risk given documented genomic instability, with structured surveillance protocols mirroring those used in MCM4 deficiency and other chromosomal-instability syndromes.

7. Evaluate whether HSCT corrects the hematologic/immune phenotype (neutropenia, NK deficiency) while recognizing it cannot address the intrinsic growth defect — clarify the risk/benefit in symptomatic patients.

Consolidated Ontology Term Suggestions

• Disease: MONDO:0044725
• Gene/protein: HGNC:28980 (GINS1); UniProt Q14691
• Phenotypes (HPO): Intrauterine growth retardation HP:0001511; Short stature HP:0004322; Neutropenia HP:0001875; NK-cell deficiency HP:0040218; Glaucoma HP:0000501; Abnormal facial shape HP:0001999
• Biological processes (GO): DNA replication GO:0006260; DNA replication initiation GO:0006270; DNA unwinding involved in DNA replication GO:0006268; cell-cycle checkpoint signaling GO:0000075; DNA replication checkpoint GO:0000076
• Cellular components (GO): CMG complex GO:0071162; GINS complex GO:0000811; nucleus GO:0005634; chromosome GO:0005694
• Cell types (CL): natural killer cell CL:0000623; neutrophil CL:0000775; hematopoietic stem cell CL:0000037
• Anatomy (UBERON): bone marrow UBERON:0002371; eye UBERON:0000970
• Treatment (NCIT): Hematopoietic stem cell transplantation NCIT:C15431 (conceptual analog); supportive care NCIT:C15277

Report compiled from 5 iterations of autonomous investigation, 8 confirmed findings, and 27 reviewed papers. Primary evidence: Cottineau et al. 2017 (PMID: 28414293) and Mackley et al. 2026 (PMID: 41689265).

Artifacts

• OpenScientist final report
• OpenScientist final report

Reference Validation

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Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:35038632 (abstract only): "The CMG [Cdc45-Mcm2-7-GINS(Psf1-3, Sld5)] helicase unwinds the double helix to separate the leading and lagging DNA strands."
• closest text in source: "The CMG [Cdc45-Mcm2-7-GINS(Psf1-3, Sld5)] helicase unwinds the double helix to separate the leading and lagging DNA strands, which are replicated by the specialized DNA polymerases epsilon (Pol ε) and delta (Pol δ), respectively"

Term Validation

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Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• HP:0001875 (3 mentions) - the report calls it "lab abnormality"; HP calls it Decreased total neutrophil count
• HP:0040218 (3 mentions) - the report calls it "lab abnormality"; HP calls it Reduced total natural killer cell count
• HP:0001511 (3 mentions) - the report calls it "clinical sign"; HP calls it Intrauterine growth retardation
• HP:0004322 (3 mentions) - the report calls it "clinical sign"; HP calls it Short stature
• HP:0001999 (2 mentions) - the report calls it "physical"; HP calls it Abnormal facial shape
• HP:0000501 (2 mentions) - the report calls it "clinical sign"; HP calls it Glaucoma
• NCIT:C15431 (2 mentions) - the report calls it "conceptual analog"; NCIT calls it Hematopoietic Cell Transplantation

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0006268 (obsolete DNA unwinding involved in DNA replication) (1 mention) - replaced by GO:0006260

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• HGNC:28980 - called "HGNC", "GINS1"