Combined Immunodeficiency Due To GINS1 Deficiency

Mendelian MONDO:0044725 Pathograph 16 Show in embeddings browser Inborn error of immunity Natural killer cell deficiency Combined immunodeficiency

Combined immunodeficiency due to GINS1 deficiency (IMD55; OMIM 617827) is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic hypomorphic variants in GINS1 (also called PSF1), one of the four subunits of the GINS complex within the eukaryotic CMG (CDC45-MCM2-7-GINS) replicative helicase. The disorder was defined in a single 2017 report of five patients from four kindreds, every one of whom showed the same triad of intrauterine growth retardation, chronic neutropenia and natural killer (NK) cell deficiency. Because complete loss of a GINS subunit is embryonic lethal, all disease alleles are partial: patient cells retain roughly 3-16% of normal GINS1 activity. That residual activity is not enough for normal replication, and patient fibroblasts show impaired GINS complex assembly, basal replication stress, impaired checkpoint signalling, defective cell cycle control and genomic instability, all rescued by wild-type GINS1. Two features make this entry mechanistically interesting rather than merely another replication-defect syndrome. First, the haematological lesion is a maturation blockade inside the bone marrow rather than peripheral destruction, and it falls on two lineages - granulocytes and NK cells - whose co-occurrence is described in the source as unusual among primary immunodeficiencies and bone marrow failures. Second, the amount of residual GINS1 activity tracks the severity of growth retardation and the in vitro cellular phenotype but does not track the immunological phenotype, which was uniform across genotypes. A single quantitative molecular defect therefore produces one dose-dependent arm and one apparently thresholded arm, which is the central open question of the entry. GINS1 sits alongside MCM4, MCM10 and GINS4 as CMG-helicase components in which biallelic hypomorphic variants cause human NK cell deficiency.

Ask OpenScientist

Ask a research question about Combined Immunodeficiency Due To GINS1 Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
10
Phenotypes
1
Hypotheses
4
Gaps
16
Pathograph
1
Genes
3
Variants
4
Medical Actions
2
Models
3
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
innate immunity defect
👪

Inheritance

1
Autosomal recessive HP:0000007
All five reported patients carry compound heterozygous GINS1 variants; parents are obligate heterozygous carriers and are unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency."
States the inheritance mode and the partial (hypomorphic) nature of the biallelic defect directly.
◈

Mechanistic Hypotheses

1
NK and granulocyte lineages are selectively vulnerable to partial CMG helicase loss
lineage_selective_replication_failure EMERGING
A single, uniform quantitative defect in replicative helicase assembly produces a strikingly non-uniform cellular outcome, sparing T and B lymphocyte numbers largely while removing NK cells and blocking granulopoiesis. The proposed explanations are that antigen-receptor-driven proliferative signals (pre-BCR, pre-TCR) rescue adaptive lineages that innate lymphoid precursors cannot access, and that DNA-integrity control may be wired differently in lineages that do not perform programmed DNA breakage. Neither has been demonstrated.
?

Discussions and Knowledge Gaps

4
Why does a ubiquitous, quantitatively uniform defect in replicative helicase assembly selectively remove the NK lineage while largely sparing T and B cell numbers?
KNOWLEDGE GAP OPEN gins1_nk_lineage_selectivity
Attached to
pathophysiology#Impaired NK Cell Differentiation
Every cell in the body needs the CMG helicase, and the defect is present in every cell, yet the immune lesion is lineage-restricted. Until this is explained, the causal edge from the cellular replication phenotype to the NK phenotype is a correlation observed across four genes (MCM4, GINS1, MCM10, GINS4) rather than a mechanism. The review literature states the question is unresolved.
Show evidence (1 reference)
PMID:36809597 SUPPORT Other
"CMG helicase function is required in any actively proliferating cell, and the reason why NK cells are seemingly particularly susceptible to damaging variants has not been elucidated."
The source states directly that the lineage selectivity is unexplained.
Why does residual GINS1 activity grade the growth phenotype but not the immunological phenotype?
KNOWLEDGE GAP OPEN gins1_activity_phenotype_dissociation
Attached to
pathophysiology#Impaired GINS/CMG Replicative Helicase Assembly pathophysiology#Restricted Somatic Growth
The same measurement (3-16% residual activity) correlates with growth retardation severity and with the in vitro cellular phenotype, yet the immunological phenotype was uniform across genotypes. Either the immune lineages sit below a threshold that even the mildest allele fails to clear, or the immune arm is driven by something other than bulk residual activity. Distinguishing these would need patients with milder alleles than any so far reported, and with n=5 the observed uniformity is also consistent with the series simply being too small to resolve a gradient.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"The levels of GINS1 activity did not influence the immunological phenotype, which was uniform."
States the dissociation between residual enzyme activity and the immune phenotype that this gap is about.
No available model reproduces the human triad of growth retardation, neutropenia and NK cell deficiency together. Does a hypomorphic Gins1 knock-in reproduce it, and specifically does it reproduce the NK deficiency?
HUMAN MODEL MISMATCH OPEN gins1_no_model_reproduces_the_triad
Attached to
pathophysiology#Bone Marrow Maturation Blockade of Granulocyte and NK Lineages pathophysiology#Impaired NK Cell Differentiation
The models split the disease rather than reproducing it. Complete GINS subunit loss in mice is embryonic lethal, so the null cannot be studied past peri-implantation. Psf1 heterozygosity gives a marrow proliferative defect, but only under 5-FU regenerative stress and with no reported NK phenotype - and the human genotype is not heterozygous null but compound hypomorphic at 3-16% residual activity, a lower dose than one intact allele. Patient fibroblasts reproduce the cellular replication phenotype faithfully but are not a haematopoietic lineage at all. The NK deficiency, which is the defining and most uniform feature of the human disease, is therefore modelled by nothing. A knock-in carrying a patient allele at patient dosage is the missing experiment, and until it exists the causal edge from the replication phenotype to the NK phenotype rests on human correlation across four CMG genes rather than on any model.
Proposed experiments
Hypomorphic Gins1 knock-in mouse with NK lineage phenotyping
gins1_hypomorphic_knockin_nk_lineage
Knock a patient GINS1 allele combination into mice to reach residual activity in the 3-16% range, then phenotype growth, neutrophil counts and NK cell development in parallel, with bone marrow progenitor immunophenotyping rather than peripheral counts alone.
Would support
pathophysiology#Impaired NK Cell Differentiation
Supporting outcome
  • A selective NK developmental block at patient-equivalent GINS1 dosage, alongside growth restriction and neutropenia, would establish the lineage selectivity as a dose-dependent property of the replication defect rather than a human-specific observation.
Refuting outcome
  • Proportionate impairment across lymphoid lineages, or an NK compartment spared at patient-equivalent dosage, would argue the human NK selectivity depends on something absent from the mouse and would redirect the question toward human NK developmental biology.
Show evidence (2 references)
PMID:24244394 SUPPORT Model Organism
"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"
Embryonic lethality of the null is the constraint that forces every model to be partial.
PMID:24244394 SUPPORT Model Organism
"However, heterozygous deletion of the SLD5 gene was found not to significantly affect bone marrow reconstitution."
A negative result in the closest available heterozygous model, demonstrating that GINS dosage reduction does not generically reproduce the marrow phenotype.
Is the GINS1 gene-disease relationship established at ClinGen "Definitive"/"Strong" level, or only at "Moderate"/"Limited"?
KNOWLEDGE GAP OPEN gins1_gene_disease_validity_consensus
Attached to
genetic#GINS1
Nine published individuals, no ClinGen gene-disease validity assertion, and a 2026 review stating explicitly that variant interpretations remain conflicting. The functional rescue data are strong for the individual alleles, but allele-level functional evidence and gene-level validity are different claims. This entry records CAUSATIVE because the alternatives in the controlled vocabulary (DISPUTED, UNKNOWN) would misstate the evidence more badly, not because Definitive/Strong has been demonstrated.
Show evidence (1 reference)
PMID:41689265 SUPPORT Human Clinical
"interpretations of implicated variants remain conflicting, demonstrating a lack of consensus around the role of GINS1 in disease"
States that the gene-disease relationship itself is not settled, which is what this gap is about.
⚙

Pathophysiology

8
Biallelic Hypomorphic GINS1 Variants
Compound heterozygous GINS1 variants reduce, but never abolish, functional GINS1 protein. Complete loss is not a possible disease state: homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice, so every viable patient genotype is a partial one.
GINS1 hgnc:28980 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased GINS1 (hgnc:28980). hgnc:28980 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Compound heterozygous hypomorphic GINS1 alleles retaining 3-16% of normal activity. Complete biallelic loss is not represented among patients and is expected to be embryonic lethal, so the disease state is necessarily partial rather than complete loss of function.
DNA replication initiation GO:0006270 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA replication initiation (GO:0006270). GO:0006270 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired GINS/CMG Replicative Helicase Assembly Reduced GINS1 protein cannot support normal assembly of the GINS complex.
Show evidence (2 references)
PMID:28414293 SUPPORT Human Clinical
"We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
Establishes the causal genotype shared by all five reported patients.
PMID:28414293 SUPPORT Model Organism
"The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice."
Mouse null data establish why only hypomorphic alleles are compatible with life, which is why this node is a partial rather than complete loss of function.
Impaired GINS/CMG Replicative Helicase Assembly
Patient fibroblasts assemble the GINS complex poorly. Residual GINS1 activity in patient cells was quantified at roughly 3% to 16% of normal and varied with genotype. Because GINS is one of the three modules of the CMG helicase, defective GINS assembly translates directly into reduced replicative helicase availability at origins.
CMG complex assembly GO:0140529 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CMG complex assembly (GO:0140529). GO:0140529 is a biological process from the Gene Ontology. ↓ DECREASED
replicative DNA helicase activity GO:0003678 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased replicative DNA helicase activity, annotated with DNA helicase activity (GO:0003678). GO:0003678 is a molecular function from the Gene Ontology. ↓ DECREASED
CMG complex GO:0071162 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased CMG complex (GO:0071162). GO:0071162 is a cellular component from the Gene Ontology.
Experimental models
Patient-derived fibroblasts with wild-type GINS1 rescue PRIMARY CELL CULTURE Patient cells carrying the actual disease genotypes show the assembly defect directly.
Downstream
Replication Stress with Impaired Checkpoint Signaling Reduced CMG helicase availability stalls and slows replication forks.
Show evidence (3 references)
PMID:28414293 SUPPORT In Vitro
"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."
Direct patient-cell demonstration of defective GINS assembly, with wild-type rescue establishing that GINS1 is the responsible component.
PMID:28414293 SUPPORT In Vitro
"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."
Quantifies the residual activity of the hypomorphic alleles and establishes a dose-response relationship with the cellular phenotype.
PMID:36809597 SUPPORT Other
"The CMG helicase is composed of 11 subunits of the CDC45-MCM-GINS complexes (12) and is responsible for unwinding double-stranded DNA and recruiting polymerases for DNA replication"
Establishes GINS as a constituent module of the CMG helicase, which is why a GINS1 defect is a replicative helicase defect.
Replication Stress with Impaired Checkpoint Signaling
Patient cells carry basal replication stress together with impaired checkpoint signalling. The combination matters: a cell under replication stress that can still signal the checkpoint arrests and repairs, whereas one that cannot signal proceeds through the cycle carrying unresolved replication problems. It is this second state that converts a quantitative shortage of helicase into genomic damage.
DNA replication checkpoint signaling GO:0000076 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA replication checkpoint signaling (GO:0000076). GO:0000076 is a biological process from the Gene Ontology. ↓ DECREASED cellular response to DNA damage stimulus GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to DNA damage stimulus, annotated with DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Defective Cell Cycle Control and Genomic Instability Unchecked replication stress propagates into cycle dysregulation and DNA damage.
Show evidence (2 references)
PMID:28414293 SUPPORT In Vitro
"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."
Reports basal replication stress and impaired checkpoint signalling as co-occurring cellular phenotypes in patient fibroblasts.
PMID:36809597 SUPPORT Other
"Replication stress, DNA damage, and cell cycle arrest are among the cellular phenotypes attributed to loss of function variants in CMG helicase proteins."
Generalizes replication stress and DNA damage as the shared cellular consequence across CMG helicase inborn errors, of which GINS1 is one.
Defective Cell Cycle Control and Genomic Instability
Patient fibroblasts show defective cell cycle control and genomic instability, both rescued by wild-type GINS1. The functional cost of this state is borne disproportionately by cell types that must undergo rapid proliferative expansion, which is the link to both the growth and the haematopoietic arms of the disease.
cell cycle checkpoint signaling GO:0000075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell cycle checkpoint signaling (GO:0000075). GO:0000075 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived fibroblasts with wild-type GINS1 rescue PRIMARY CELL CULTURE Re-expression of wild-type GINS1 reverses the cellular phenotype, which is the causal test rather than an observation.
Downstream
Bone Marrow Maturation Blockade of Granulocyte and NK Lineages Proliferation-dependent haematopoietic maturation fails, producing the combined neutropenia and NK cell deficiency.
Restricted Somatic Growth Reduced proliferative capacity across somatic tissues restricts intrauterine and postnatal growth, in a manner graded by residual GINS1 activity.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
Reports defective cell cycle control and genomic instability in patient cells, with wild-type GINS1 rescue confirming causality.
Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
The neutropenia and the NK cell deficiency are both central, not peripheral: the source locates the defect as a blockade in the bone marrow. This is the entry's defining lesion, and the co-occurrence of these two particular lineages is explicitly noted as unusual among primary immunodeficiencies and bone marrow failures.
hematopoietic multipotent progenitor cell CL:0000837 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic multipotent progenitor cell (CL:0000837). CL:0000837 is a cell type from the Cell Ontology.
granulocyte differentiation GO:0030851 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased granulocyte differentiation (GO:0030851). GO:0030851 is a biological process from the Gene Ontology. ↓ DECREASED natural killer cell differentiation GO:0001779 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased natural killer cell differentiation (GO:0001779). GO:0001779 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Psf1 (Gins1) heterozygous mouse Mouse partially recapitulates Reproduces a marrow proliferative failure from reduced Psf1 dosage, but only under regenerative stress and without the NK-lineage specificity that defines the human disease.
Downstream
Impaired NK Cell Differentiation The marrow blockade removes the NK lineage's developmental output.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"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."
Locates the lesion in the bone marrow rather than the periphery, and records the unusual pairing of the two affected lineages.
Impaired NK Cell Differentiation
NK cells are disproportionately affected relative to other lymphoid lineages, a pattern shared across the CMG-helicase immunodeficiencies. Why remains unresolved; the review literature states plainly that the reason has not been elucidated. Two hypotheses raised in the source are that pre-BCR/pre-TCR signalling gives developing B and T cells a proliferative rescue that innate lymphoid precursors lack, and that DNA-integrity machinery may simply be regulated differently in lineages that do not undergo antigen-receptor rearrangement.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
natural killer cell differentiation GO:0001779 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased natural killer cell differentiation (GO:0001779). GO:0001779 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Susceptibility to Herpesvirus and Other Viral Infection Loss of NK effector output impairs control of herpesviruses in particular.
Show evidence (2 references)
PMID:36809597 SUPPORT Other
"Specifically, NKD due to helicase variants manifests as impaired NK cell differentiation and maturation leading to significant functional impairment and resulting viral infections in affected individuals"
States the shared NK differentiation lesion across the CMG helicase immunodeficiencies, GINS1 among them.
PMID:36809597 SUPPORT Other
"CMG helicase function is required in any actively proliferating cell, and the reason why NK cells are seemingly particularly susceptible to damaging variants has not been elucidated."
Records explicitly that the lineage selectivity of this mechanism is unexplained, which is the substance of the knowledge gap below.
Susceptibility to Herpesvirus and Other Viral Infection
The clinical consequence of NK deficiency is disproportionate difficulty controlling herpesviruses, whose principal immune-evasion strategy - downregulating HLA class I - is precisely what renders an infected cell visible to NK cells. Reported patients had prolonged acute CMV and varicella zoster infections, severe necrotizing varicella, and recurrent herpes simplex episodes.
Show evidence (1 reference)
PMID:36809597 SUPPORT Other
"It is thought that herpes viruses act to evade cytotoxic T lymphocyte responses primarily by downregulating HLA-I expression in infected host cells, which consequently renders them susceptible to killing by natural killer cells"
Gives the immunological reason why NK deficiency produces a herpesvirus-weighted rather than a general infection susceptibility.
Restricted Somatic Growth
Growth restriction begins in utero and in most patients continues after birth. Unlike the immunological arm, this arm is dose-dependent: severity tracked the residual GINS1 activity measured in patient cells. In one patient the growth failure was refractory to enteral, parenteral and growth hormone support, indicating a cell-intrinsic proliferative limit rather than a nutritional deficit.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
Establishes the dose-dependence of the growth arm on residual GINS1 activity, in contrast to the immunological arm. Graded IN_VITRO because the quoted measurement is made in patient-derived cells; the clinical growth phenotype it is correlated against is reported elsewhere.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Combined Immunodeficiency Due To GINS1 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Blood 2
Chronic Neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality chronic. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
Reports chronic neutropenia in all five patients.
Bone Marrow Dysplasia Myelodysplasia HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"Myelodysplasia was documented in bone marrow analysis."
Documents marrow dysplasia in P5, the histological counterpart of the maturation blockade.
Digestive 1
Protein-Losing Enteropathy HP:0002243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein-losing enteropathy (HP:0002243). HP:0002243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"The diarrhea was associated with severe protein-losing enteropathy."
Records the association of P3's diarrhoea with severe protein-losing enteropathy.
Eye 1
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41689265 SUPPORT Human Clinical
"glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion"
Records glaucoma across more than one unrelated individual and the authors' own framing of it as a candidate phenotypic expansion.
PMID:41689265 SUPPORT Human Clinical
"unilateral congenital glaucoma, causing secondary high myopia"
Describes the specific ocular phenotype in the 2026 proband.
Head and Neck 1
Mild Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"dation (intra- and extrauterine) and mild facial dysmorphism, except patient 4 (P4; no extrauterine growth retardation)"
Records mild facial dysmorphism accompanying the growth retardation, and names P4 as the exception for extrauterine growth. The quote opens mid-word because the source PDF hyphenates "retar-|dation" across a line break.
Growth 2
Intrauterine Growth Retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
Reports intrauterine growth retardation in all five patients.
Postnatal Growth Retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"Four of the 5 patients also had postnatal growth retardation."
Reports postnatal growth retardation in four of five patients, which is why this is recorded as frequent but not obligate.
Other 3
Natural Killer Cell Deficiency Reduced total natural killer cell count HP:0040218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced natural killer cell count, annotated with Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent Severe Viral Infection
Show evidence (2 references)
PMID:28414293 SUPPORT Human Clinical
"We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
Reports NK cell deficiency in all five patients.
PMID:41689265 SUPPORT Human Clinical
"She has overlapping features with the previously reported individuals, cementing growth retardation, neutropenia, and natural killer cell deficiency as core features."
Independent confirmation from the 2026 review that NK cell deficiency is a core rather than incidental feature across the published cohort.
Recurrent Severe Viral Infection Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28414293 SUPPORT Human Clinical
"infections with viruses but also some documented cases of bacterial infection"
Records that the reported infection burden comprised viral infections together with documented bacterial infections.
PMID:41689265 REFUTE Human Clinical
"our proband, unlike the others, has no history of infections"
Recorded as REFUTE against recurrent infection being an obligate feature: at least one genetically confirmed individual has had no infections at all. This does not contradict the infections reported in the 2017 series - it establishes that infection burden is variable and that a normal infection history does not exclude the diagnosis.
Reduced CD8-Positive T Cell Count in Early Childhood Decreased total CD8+ T cell count HP:5210426 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating CD8-positive T cell count, annotated with Decreased total CD8+ T cell count (HP:5210426), qualified as infantile onset. HP:5210426 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"During the first 3 years of life, the two patients tested (P2 and P3) displayed low counts of blood T cells, especially CD8+ T cells."
Reports the reduced blood T cell counts, most marked for CD8+ T cells, in the two patients tested during the first three years of life.
🧬

Genetic Associations

1
GINS1
Gene: GINS1 hgnc:28980 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GINS1 (hgnc:28980). hgnc:28980 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:28414293 SUPPORT Human Clinical
"We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
Establishes GINS1 as the causal gene and the compound heterozygous allelic architecture.
PMID:28414293 SUPPORT In Vitro
"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."
Quantifies the hypomorphic residual activity and its genotype dependence.
🔬

Variants

3
GINS1 c.247C>T (p.Arg83Cys) Pathogenic
Gene: GINS1 hgnc:28980 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in GINS1 (hgnc:28980). hgnc:28980 is a gene from the HUGO Gene Nomenclature Committee. SNV
Missense variant in exon 4 replacing arginine with cysteine at position 83. Predicted damaging with a CADD score of 35 against a GINS1-specific mutation significance cutoff of 16.5. Both missense alleles are present in ExAC at low minor allele frequencies, so unlike the 5' UTR alleles they are not absent from population reference data - consistent with hypomorphic rather than null alleles.
Show evidence (3 references)
PMID:28414293 SUPPORT Human Clinical
"nine with a cysteine residue in position 83 (p.R83C), a change pre- dicted to be damaging (CADD score 35"
Records the p.R83C substitution and its CADD score. The quote opens and closes mid-word because the source PDF hyphenates "argi-|nine" and "pre-|dicted" across line breaks.
PMID:28414293 SUPPORT Other
"Both the R83C and C152Y substitutions were reported in the Exome Aggregation Consortium (ExAC) database"
Documents that both missense alleles appear in ExAC, the population reference dataset available at the time of the founding report.
PMID:41689265 SUPPORT Other
"This variant is observed at an allele frequency of 0.066% in population controls in the Genome Aggregation Database (gnomAD), with a maximum allele frequency of 0.4% in the European (Finnish) population."
Updated population frequency from gnomAD. The 0.4% Finnish maximum is high for a recessive disease allele and is the main reason this variant is best read as hypomorphic rather than null - a true null at that frequency would be expected to produce homozygotes, which are not observed.
GINS1 c.455G>A (p.Cys152Tyr) Pathogenic
Gene: GINS1 hgnc:28980 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in GINS1 (hgnc:28980). hgnc:28980 is a gene from the HUGO Gene Nomenclature Committee. SNV
Missense variant in exon 6 replacing cysteine with tyrosine at position 152, predicted damaging with a CADD score of 32.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"a c.455G>A substitution in exon 6 leading to the replacement of a cysteine with a tyrosine residue in position 152 (p.C152Y)"
Records the c.455G>A change and the residue it substitutes.
GINS1 5' UTR substitutions at positions -48 and -60
Gene: GINS1 hgnc:28980 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in GINS1 (hgnc:28980). hgnc:28980 is a gene from the HUGO Gene Nomenclature Committee. SNV LOE
Two non-coding substitutions in the 5' untranslated region, at positions -48 and -60 relative to the ATG. These are the regulatory arm of the allelic spectrum and are the reason the disease is expressed as reduced rather than absent GINS1: a promoter/UTR-level reduction in expression leaves residual protein where a coding null would not.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"and p.C152Y) and two 5′ UTR nucleotide substitutions (at posi- tions -48 and -60 relative to the ATG"
Records the two 5' UTR substitutions and their positions relative to the ATG. The quote preserves the source's "posi-|tions" hyphen break.
💊

Medical Actions

4
Granulocyte Colony-Stimulating Factor
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: granulocyte colony-stimulating factor NCIT:C1287 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses granulocyte colony-stimulating factor, annotated with Recombinant Granulocyte Colony-Stimulating Factor (NCIT:C1287). NCIT:C1287 is a therapeutic agent from the NCI Thesaurus.
Used in P5 for the chronic neutropenia. The source records the treatment, not a measured response, so this is documented management rather than demonstrated efficacy. Modality is `OTHER` rather than `PROTEIN_REPLACEMENT`: recombinant G-CSF is given to stimulate granulopoiesis pharmacologically, and these patients are not G-CSF deficient - the lesion is downstream of the cytokine.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"Patient P5 was treated by G-CSF."
Documents G-CSF use in one reported patient. No response measure is reported, so no efficacy claim is made here.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Initiated in P3 for low serum IgM and IgG driven by protein-losing enteropathy, together with antibiotic prophylaxis. The reported effect - a large reduction in airway infection frequency - is attributed to the combination, not to either component alone.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"immunoglobulin replacement and antibiotic prophylaxis were initiated, greatly decreasing the frequency of airway infections."
Records the initiation of immunoglobulin replacement together with antibiotic prophylaxis, and the reported effect. The effect is attributed to the combination, not to either component alone.
Antimicrobial Prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trimethoprim CHEBI:45924 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trimethoprim (CHEBI:45924). CHEBI:45924 is a therapeutic agent from Chemical Entities of Biological Interest. sulfamethoxazole CHEBI:9332 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sulfamethoxazole (CHEBI:9332). CHEBI:9332 is a therapeutic agent from Chemical Entities of Biological Interest.
Trimethoprim/sulfamethoxazole prophylaxis was given to P4 from age 15 to 24 years; antibiotic prophylaxis was also part of P3's regimen.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"She received prophylactic antibiotic treatment (trimethoprim/sulfamethoxazole) from 15 to 24 years of age."
Documents the specific agents and the duration of antimicrobial prophylaxis in P4, which is what the bound CHEBI agents rest on.
Enteral and Parenteral Nutritional Support
Action: nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Attempted for the growth failure, and notable for failing. P3's growth retardation did not respond to enteral feeding support including percutaneous endoscopic gastrostomy, or to parenteral feeding. Recorded because the negative result is mechanistically informative: it argues the growth arm is a cell-intrinsic proliferative limit rather than a nutritional deficit.
Show evidence (1 reference)
PMID:28414293 REFUTE Human Clinical
"The growth retardation was extremely pronounced and did not respond to enteral feeding support including percutaneous endoscopic gastrostomy (PEG) feed- ing or to parenteral feeding."
Reports failure of nutritional support, including PEG and parenteral feeding, to correct the growth retardation. Recorded as REFUTE because it is a negative result about this intervention, and it is mechanistically informative: the growth arm is a cell-intrinsic proliferative limit, not a nutritional one. The quote preserves the source's "feed- ing" hyphen break.
🔬

Diagnosis

3
Lymphocyte Subset Immunophenotyping
Flow cytometric enumeration of NK cells is the entry point: a profoundly reduced NK count in a child with intrauterine growth retardation and chronic neutropenia is the syndrome's recognisable signature, and the pairing is the discriminating feature.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"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."
The unusual pairing of neutropenia with NK cell deficiency is what makes the combined immunophenotype diagnostically informative.
Bone Marrow Examination
Marrow analysis distinguishes a central maturation blockade from peripheral consumption and shows the dysplastic changes reported in several patients.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"Myelodysplasia was documented in bone marrow analysis."
Marrow examination is what demonstrated the dysplastic changes underlying the peripheral cytopenias.
Molecular Genetic Testing of GINS1
Confirmatory. Biallelic GINS1 variants establish the diagnosis; because complete loss of function is lethal, a plausible genotype must retain residual activity on at least one allele.
Show evidence (1 reference)
PMID:28414293 SUPPORT Human Clinical
"We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
Biallelic GINS1 variants are the molecular diagnostic criterion.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Nine individuals published to date. No incidence or prevalence estimate exists and none is computable from a cohort of this size.
Show evidence (1 reference)
PMID:41689265 SUPPORT Human Clinical
"We additionally present a review of all nine individuals reported to date."
Establishes the size of the published cohort as of 2026.
🧫

Experimental Models

1
Patient-derived fibroblasts with wild-type GINS1 rescue PRIMARY_CELL_CULTURE
The system that carries most of this entry's mechanistic weight. Primary fibroblasts from affected individuals reproduce the cellular phenotype - impaired GINS complex assembly, basal replication stress, impaired checkpoint signalling, defective cell cycle control and genomic instability - and re-expressing wild-type GINS1 reverses it. The rescue arm is what converts a set of correlated abnormalities in patient cells into a causal claim about GINS1.
Publication
PMID:28414293
Pathograph links
Impaired GINS/CMG Replicative Helicase Assembly recapitulates fidelity: high Patient cells carrying the actual disease genotypes show the assembly defect directly.
Limitations: Fibroblasts are not a haematopoietic lineage, so the model speaks to the general replication defect and to the growth arm, not to the marrow maturation blockade that defines the disease clinically. Cultured fibroblasts also proliferate under conditions unlike those of a differentiating progenitor in vivo.
Readouts
GINS complex assembly
Direction: DECREASED
Interpretation: Direct measurement of the molecular defect in patient cells.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
Reports impaired GINS complex assembly in patient fibroblasts.
Residual GINS1 activity
Direction: DECREASED
Interpretation: Quantifies how much function the hypomorphic alleles retain, which is the disease-relevant quantity.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
Reports the residual activity range and its genotype dependence.
Defective Cell Cycle Control and Genomic Instability rescues fidelity: high Re-expression of wild-type GINS1 reverses the cellular phenotype, which is the causal test rather than an observation.
Limitations: Rescue is by transgenic overexpression rather than by correcting the endogenous alleles, so it establishes sufficiency of wild-type GINS1 but not the dose at which the phenotype would resolve.
Readouts
Cell cycle control and genomic instability
Direction: RESTORED
Interpretation: The rescue arm; reversal on wild-type re-expression.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
The same sentence reports the defects and their reversal by wild-type GINS1; the rescue clause is what this readout records.
Show evidence (1 reference)
PMID:28414293 SUPPORT In Vitro
"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."
Establishes patient fibroblasts with wild-type rescue as the system in which the cellular mechanism was demonstrated.
🐁

Animal Models

1
Psf1 (Gins1) heterozygous mouse
Two things make this model informative, and they pull in opposite directions. Psf1 haploinsufficiency causes failure of acute bone marrow haematopoietic stem cell proliferation during reconstitution after 5-FU ablation - the closest animal counterpart to the human marrow phenotype. But heterozygous deletion of Sld5, another GINS subunit, does not significantly affect bone marrow reconstitution, so the marrow requirement is not a generic property of GINS dosage.
Species
Mouse
Genotype
Psf1 heterozygous; Sld5 (Gins4) heterozygous and null comparators
Publication
PMID:24244394
Pathograph links
Bone Marrow Maturation Blockade of Granulocyte and NK Lineages partially recapitulates fidelity: moderate Reproduces a marrow proliferative failure from reduced Psf1 dosage, but only under regenerative stress and without the NK-lineage specificity that defines the human disease.
Limitations: The mouse phenotype is elicited by 5-FU ablation rather than arising at baseline, so it models regenerative demand rather than the steady-state maturation blockade seen in patients. NK cell numbers are not reported. Mouse Psf1 heterozygosity is also not the human genotype: patients are compound heterozygous for hypomorphic alleles retaining 3-16% activity, which is a different and lower dose than one intact allele.
Readouts
Bone marrow HSC proliferation after 5-FU ablation
Direction: DECREASED
Interpretation: Marrow proliferative failure attributable to reduced Psf1 dosage.
Show evidence (1 reference)
PMID:24244394 SUPPORT Model Organism
"We have previously reported that 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."
Reports the marrow proliferative defect in Psf1 heterozygotes.
Bone marrow reconstitution in Sld5 heterozygotes
Direction: UNCHANGED
Interpretation: A real negative result. Reduced dosage of a different GINS subunit does not reproduce the marrow phenotype, so the requirement is subunit-specific rather than a general consequence of GINS haploinsufficiency.
Show evidence (1 reference)
PMID:24244394 SUPPORT Model Organism
"However, heterozygous deletion of the SLD5 gene was found not to significantly affect bone marrow reconstitution."
Records the negative result for Sld5 heterozygotes, which is what makes the Psf1 finding subunit-specific.
Show evidence (1 reference)
PMID:24244394 SUPPORT Model Organism
"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"
Establishes the embryonic lethality of complete GINS-subunit loss in mice, which is why every viable human genotype is hypomorphic.
{ }

Source YAML

click to show 
name: Combined Immunodeficiency Due To GINS1 Deficiency
creation_date: "2026-08-30T18:30:00Z"
category: Mendelian
disease_term:
  preferred_term: combined immunodeficiency due to GINS1 deficiency
  term:
    id: MONDO:0044725
    label: combined immunodeficiency due to GINS1 deficiency
description: >
  Combined immunodeficiency due to GINS1 deficiency (IMD55; OMIM 617827) is an
  ultra-rare autosomal recessive inborn error of immunity caused by biallelic
  hypomorphic variants in GINS1 (also called PSF1), one of the four subunits of
  the GINS complex within the eukaryotic CMG (CDC45-MCM2-7-GINS) replicative
  helicase. The disorder was defined in a single 2017 report of five patients
  from four kindreds, every one of whom showed the same triad of intrauterine
  growth retardation, chronic neutropenia and natural killer (NK) cell
  deficiency. Because complete loss of a GINS subunit is embryonic lethal, all
  disease alleles are partial: patient cells retain roughly 3-16% of normal
  GINS1 activity. That residual activity is not enough for normal replication,
  and patient fibroblasts show impaired GINS complex assembly, basal
  replication stress, impaired checkpoint signalling, defective cell cycle
  control and genomic instability, all rescued by wild-type GINS1.

  Two features make this entry mechanistically interesting rather than merely
  another replication-defect syndrome. First, the haematological lesion is a
  maturation blockade inside the bone marrow rather than peripheral
  destruction, and it falls on two lineages - granulocytes and NK cells - whose
  co-occurrence is described in the source as unusual among primary
  immunodeficiencies and bone marrow failures. Second, the amount of residual
  GINS1 activity tracks the severity of growth retardation and the in vitro
  cellular phenotype but does not track the immunological phenotype, which was
  uniform across genotypes. A single quantitative molecular defect therefore
  produces one dose-dependent arm and one apparently thresholded arm, which is
  the central open question of the entry.

  GINS1 sits alongside MCM4, MCM10 and GINS4 as CMG-helicase components in
  which biallelic hypomorphic variants cause human NK cell deficiency.

synonyms:
  - IMD55
  - immunodeficiency 55
  - CID due to GINS1 deficiency
  - GINS1 deficiency
  - combined immunodeficiency with intrauterine growth retardation-NK cell deficiency-neutropenia

parents:
  - Inborn error of immunity
  - Natural killer cell deficiency
  - Combined immunodeficiency

classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:36809597
      reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Though rare, the deficiency of several genes has been described as underlying causes of NKD, including MCM4, GINS1, MCM10, and GINS4, all of which are involved in the eukaryotic CMG helicase."
      explanation: >
        Places GINS1 deficiency among the inborn errors of immunity that cause
        NK cell deficiency, which is Harrison's immune/rheumatologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:28414293
      reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
      explanation: >
        A biallelic Mendelian disorder defined by compound heterozygous GINS1
        variants, placing it in Harrison's genetics Part.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      Grouped with MCM4, MCM10 and GINS4 as CMG-helicase causes of NK cell
      deficiency, an innate-immunity defect. Note the tension with the MONDO
      label and the OMIM title, both of which call this a *combined*
      immunodeficiency: the T-cell compartment is measurably affected (low
      CD8+ T cells in early childhood in the two patients tested, slightly
      reduced in vitro T-cell proliferation in all patients), so the
      combined-immunodeficiency label is not simply wrong. The IUIS placement
      here reflects which lineage carries the defining and most consistent
      lesion, not a claim that T cells are spared.
    evidence:
    - reference: PMID:36809597
      reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Natural killer cell deficiency (NKD) is one such IEI where natural killer (NK) cells are the main immune lineage affected."
      explanation: >-
        Frames NKD as an inborn error of immunity acting principally on an
        innate effector lineage, which is the basis for the IUIS innate/intrinsic
        immunity assignment.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    All five reported patients carry compound heterozygous GINS1 variants;
    parents are obligate heterozygous carriers and are unaffected.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency."
    explanation: >
      States the inheritance mode and the partial (hypomorphic) nature of the
      biallelic defect directly.

notes: >
  Ultra-rare. The disease-defining series is five patients from four kindreds
  (Cottineau et al., J Clin Invest 2017); a 2026 review (Mackley et al., Clin
  Genet) puts the total published cohort at nine individuals. Numbers
  throughout this entry are therefore counts out of five or out of nine, never
  frequencies, and every `frequency` value is left unset rather than computed
  from a cohort this small. Where a claim comes from the 2017 series the
  denominator is five; where it comes from the 2026 review it is nine. Individual
  patients also carried findings that are almost certainly not part of the
  core syndrome (osteosarcoma in P2, glaucoma in P5); these are recorded with
  that caveat rather than presented as disease features.

  Haematopoietic stem cell transplantation is deliberately NOT curated as a
  treatment. It is the conceptual analogue from other combined
  immunodeficiencies, but no reported GINS1 patient has been transplanted, and
  transplantation would not address the growth arm, which is a cell-intrinsic
  replication defect present in every tissue rather than a haematopoietic one.
  Recording it with no evidence would imply a standard of care that does not
  exist for this disease. This is a decision, not an oversight.

  No `conforms_to` was declared. The obvious candidate module,
  `genomic_instability_aging`, is explicitly framed for the aging process and
  its natural conformers are the DNA-repair-deficiency progeroid syndromes;
  GINS1 deficiency is a constitutional replication-initiation defect whose
  output is a developmental and haematopoietic maturation failure, not
  age-dependent damage accumulation. Forcing conformance would have asserted a
  chain the source does not support. If a replication-stress module facing
  development rather than aging is ever created, this entry and IMD80 (MCM10)
  are its first two conformers.

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Nine individuals published to date. No incidence or prevalence estimate
    exists and none is computable from a cohort of this size.
  evidence:
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We additionally present a review of all nine individuals reported to date."
    explanation: >-
      Establishes the size of the published cohort as of 2026.

pathophysiology:
- name: Biallelic Hypomorphic GINS1 Variants
  biological_scale: MOLECULAR
  description: >
    Compound heterozygous GINS1 variants reduce, but never abolish, functional
    GINS1 protein. Complete loss is not a possible disease state: homozygous
    null mutations of GINS component-encoding genes are embryonic lethal in
    mice, so every viable patient genotype is a partial one.
  genes:
  - preferred_term: GINS1
    term:
      id: hgnc:28980
      label: GINS1
    modifier: DECREASED
  genetic_context:
    description: >-
      Compound heterozygous hypomorphic GINS1 alleles retaining 3-16% of
      normal activity. Complete biallelic loss is not represented among
      patients and is expected to be embryonic lethal, so the disease state
      is necessarily partial rather than complete loss of function.
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: DNA replication initiation
    modifier: DECREASED
    term:
      id: GO:0006270
      label: DNA replication initiation
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
    explanation: >
      Establishes the causal genotype shared by all five reported patients.
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice."
    explanation: >
      Mouse null data establish why only hypomorphic alleles are compatible
      with life, which is why this node is a partial rather than complete
      loss of function.
  downstream:
  - target: Impaired GINS/CMG Replicative Helicase Assembly
    description: Reduced GINS1 protein cannot support normal assembly of the GINS complex.

- name: Impaired GINS/CMG Replicative Helicase Assembly
  biological_scale: MOLECULAR
  description: >
    Patient fibroblasts assemble the GINS complex poorly. Residual GINS1
    activity in patient cells was quantified at roughly 3% to 16% of normal
    and varied with genotype. Because GINS is one of the three modules of the
    CMG helicase, defective GINS assembly translates directly into reduced
    replicative helicase availability at origins.
  molecular_functions:
  - preferred_term: replicative DNA helicase activity
    modifier: DECREASED
    term:
      id: GO:0003678
      label: DNA helicase activity
  cellular_components:
  - preferred_term: CMG complex
    modifier: DECREASED
    term:
      id: GO:0071162
      label: CMG complex
  biological_processes:
  - preferred_term: CMG complex assembly
    modifier: DECREASED
    term:
      id: GO:0140529
      label: CMG complex assembly
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Direct patient-cell demonstration of defective GINS assembly, with
      wild-type rescue establishing that GINS1 is the responsible component.
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Quantifies the residual activity of the hypomorphic alleles and
      establishes a dose-response relationship with the cellular phenotype.
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The CMG helicase is composed of 11 subunits of the CDC45-MCM-GINS complexes (12) and is responsible for unwinding double-stranded DNA and recruiting polymerases for DNA replication"
    explanation: >
      Establishes GINS as a constituent module of the CMG helicase, which is
      why a GINS1 defect is a replicative helicase defect.
  downstream:
  - target: Replication Stress with Impaired Checkpoint Signaling
    description: Reduced CMG helicase availability stalls and slows replication forks.

- name: Replication Stress with Impaired Checkpoint Signaling
  biological_scale: CELLULAR
  description: >
    Patient cells carry basal replication stress together with impaired
    checkpoint signalling. The combination matters: a cell under replication
    stress that can still signal the checkpoint arrests and repairs, whereas
    one that cannot signal proceeds through the cycle carrying unresolved
    replication problems. It is this second state that converts a quantitative
    shortage of helicase into genomic damage.
  biological_processes:
  - preferred_term: DNA replication checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0000076
      label: DNA replication checkpoint signaling
  - preferred_term: cellular response to DNA damage stimulus
    modifier: INCREASED
    term:
      id: GO:0006974
      label: DNA damage response
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Reports basal replication stress and impaired checkpoint signalling as
      co-occurring cellular phenotypes in patient fibroblasts.
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Replication stress, DNA damage, and cell cycle arrest are among the cellular phenotypes attributed to loss of function variants in CMG helicase proteins."
    explanation: >
      Generalizes replication stress and DNA damage as the shared cellular
      consequence across CMG helicase inborn errors, of which GINS1 is one.
  downstream:
  - target: Defective Cell Cycle Control and Genomic Instability
    description: Unchecked replication stress propagates into cycle dysregulation and DNA damage.

- name: Defective Cell Cycle Control and Genomic Instability
  biological_scale: CELLULAR
  description: >
    Patient fibroblasts show defective cell cycle control and genomic
    instability, both rescued by wild-type GINS1. The functional cost of this
    state is borne disproportionately by cell types that must undergo rapid
    proliferative expansion, which is the link to both the growth and the
    haematopoietic arms of the disease.
  biological_processes:
  - preferred_term: cell cycle checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Reports defective cell cycle control and genomic instability in patient
      cells, with wild-type GINS1 rescue confirming causality.
  downstream:
  - target: Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
    description: >
      Proliferation-dependent haematopoietic maturation fails, producing the
      combined neutropenia and NK cell deficiency.
  - target: Restricted Somatic Growth
    description: >
      Reduced proliferative capacity across somatic tissues restricts intrauterine
      and postnatal growth, in a manner graded by residual GINS1 activity.

- name: Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
  biological_scale: TISSUE
  description: >
    The neutropenia and the NK cell deficiency are both central, not
    peripheral: the source locates the defect as a blockade in the bone
    marrow. This is the entry's defining lesion, and the co-occurrence of
    these two particular lineages is explicitly noted as unusual among primary
    immunodeficiencies and bone marrow failures.
  cell_types:
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: granulocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030851
      label: granulocyte differentiation
  - preferred_term: natural killer cell differentiation
    modifier: DECREASED
    term:
      id: GO:0001779
      label: natural killer cell differentiation
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      Locates the lesion in the bone marrow rather than the periphery, and
      records the unusual pairing of the two affected lineages.
  downstream:
  - target: Impaired NK Cell Differentiation
    description: The marrow blockade removes the NK lineage's developmental output.

- name: Impaired NK Cell Differentiation
  biological_scale: CELLULAR
  description: >
    NK cells are disproportionately affected relative to other lymphoid
    lineages, a pattern shared across the CMG-helicase immunodeficiencies.
    Why remains unresolved; the review literature states plainly that the
    reason has not been elucidated. Two hypotheses raised in the source are
    that pre-BCR/pre-TCR signalling gives developing B and T cells a
    proliferative rescue that innate lymphoid precursors lack, and that
    DNA-integrity machinery may simply be regulated differently in lineages
    that do not undergo antigen-receptor rearrangement.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell differentiation
    modifier: DECREASED
    term:
      id: GO:0001779
      label: natural killer cell differentiation
  evidence:
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Specifically, NKD due to helicase variants manifests as impaired NK cell differentiation and maturation leading to significant functional impairment and resulting viral infections in affected individuals"
    explanation: >
      States the shared NK differentiation lesion across the CMG helicase
      immunodeficiencies, GINS1 among them.
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CMG helicase function is required in any actively proliferating cell, and the reason why NK cells are seemingly particularly susceptible to damaging variants has not been elucidated."
    explanation: >
      Records explicitly that the lineage selectivity of this mechanism is
      unexplained, which is the substance of the knowledge gap below.
  downstream:
  - target: Susceptibility to Herpesvirus and Other Viral Infection
    description: Loss of NK effector output impairs control of herpesviruses in particular.

- name: Susceptibility to Herpesvirus and Other Viral Infection
  biological_scale: ORGANISM
  description: >
    The clinical consequence of NK deficiency is disproportionate difficulty
    controlling herpesviruses, whose principal immune-evasion strategy -
    downregulating HLA class I - is precisely what renders an infected cell
    visible to NK cells. Reported patients had prolonged acute CMV and
    varicella zoster infections, severe necrotizing varicella, and recurrent
    herpes simplex episodes.
  evidence:
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is thought that herpes viruses act to evade cytotoxic T lymphocyte responses primarily by downregulating HLA-I expression in infected host cells, which consequently renders them susceptible to killing by natural killer cells"
    explanation: >
      Gives the immunological reason why NK deficiency produces a
      herpesvirus-weighted rather than a general infection susceptibility.

- name: Restricted Somatic Growth
  biological_scale: ORGANISM
  description: >
    Growth restriction begins in utero and in most patients continues after
    birth. Unlike the immunological arm, this arm is dose-dependent: severity
    tracked the residual GINS1 activity measured in patient cells. In one
    patient the growth failure was refractory to enteral, parenteral and
    growth hormone support, indicating a cell-intrinsic proliferative limit
    rather than a nutritional deficit.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Establishes the dose-dependence of the growth arm on residual GINS1
      activity, in contrast to the immunological arm. Graded IN_VITRO because
      the quoted measurement is made in patient-derived cells; the clinical
      growth phenotype it is correlated against is reported elsewhere.

mechanistic_hypotheses:
- hypothesis_group_id: lineage_selective_replication_failure
  hypothesis_label: NK and granulocyte lineages are selectively vulnerable to partial CMG helicase loss
  status: EMERGING
  description: >
    A single, uniform quantitative defect in replicative helicase assembly
    produces a strikingly non-uniform cellular outcome, sparing T and B
    lymphocyte numbers largely while removing NK cells and blocking
    granulopoiesis. The proposed explanations are that antigen-receptor-driven
    proliferative signals (pre-BCR, pre-TCR) rescue adaptive lineages that
    innate lymphoid precursors cannot access, and that DNA-integrity control
    may be wired differently in lineages that do not perform programmed
    DNA breakage. Neither has been demonstrated.

discussions:
- discussion_id: gins1_nk_lineage_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired NK Cell Differentiation
  prompt: >-
    Why does a ubiquitous, quantitatively uniform defect in replicative
    helicase assembly selectively remove the NK lineage while largely sparing
    T and B cell numbers?
  rationale: >-
    Every cell in the body needs the CMG helicase, and the defect is present
    in every cell, yet the immune lesion is lineage-restricted. Until this is
    explained, the causal edge from the cellular replication phenotype to the
    NK phenotype is a correlation observed across four genes (MCM4, GINS1,
    MCM10, GINS4) rather than a mechanism. The review literature states the
    question is unresolved.
  evidence:
  - reference: PMID:36809597
    reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CMG helicase function is required in any actively proliferating cell, and the reason why NK cells are seemingly particularly susceptible to damaging variants has not been elucidated."
    explanation: >-
      The source states directly that the lineage selectivity is unexplained.

- discussion_id: gins1_activity_phenotype_dissociation
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired GINS/CMG Replicative Helicase Assembly
  - pathophysiology#Restricted Somatic Growth
  prompt: >-
    Why does residual GINS1 activity grade the growth phenotype but not the
    immunological phenotype?
  rationale: >-
    The same measurement (3-16% residual activity) correlates with growth
    retardation severity and with the in vitro cellular phenotype, yet the
    immunological phenotype was uniform across genotypes. Either the immune
    lineages sit below a threshold that even the mildest allele fails to
    clear, or the immune arm is driven by something other than bulk residual
    activity. Distinguishing these would need patients with milder alleles
    than any so far reported, and with n=5 the observed uniformity is also
    consistent with the series simply being too small to resolve a gradient.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The levels of GINS1 activity did not influence the immunological phenotype, which was uniform."
    explanation: >-
      States the dissociation between residual enzyme activity and the immune
      phenotype that this gap is about.

- discussion_id: gins1_no_model_reproduces_the_triad
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
  - pathophysiology#Impaired NK Cell Differentiation
  prompt: >-
    No available model reproduces the human triad of growth retardation,
    neutropenia and NK cell deficiency together. Does a hypomorphic Gins1
    knock-in reproduce it, and specifically does it reproduce the NK
    deficiency?
  rationale: >-
    The models split the disease rather than reproducing it. Complete GINS
    subunit loss in mice is embryonic lethal, so the null cannot be studied
    past peri-implantation. Psf1 heterozygosity gives a marrow proliferative
    defect, but only under 5-FU regenerative stress and with no reported NK
    phenotype - and the human genotype is not heterozygous null but compound
    hypomorphic at 3-16% residual activity, a lower dose than one intact
    allele. Patient fibroblasts reproduce the cellular replication phenotype
    faithfully but are not a haematopoietic lineage at all. The NK deficiency,
    which is the defining and most uniform feature of the human disease, is
    therefore modelled by nothing. A knock-in carrying a patient allele at
    patient dosage is the missing experiment, and until it exists the causal
    edge from the replication phenotype to the NK phenotype rests on human
    correlation across four CMG genes rather than on any model.
  proposed_experiments:
  - experiment_id: gins1_hypomorphic_knockin_nk_lineage
    name: Hypomorphic Gins1 knock-in mouse with NK lineage phenotyping
    description: >-
      Knock a patient GINS1 allele combination into mice to reach residual
      activity in the 3-16% range, then phenotype growth, neutrophil counts and
      NK cell development in parallel, with bone marrow progenitor
      immunophenotyping rather than peripheral counts alone.
    would_support:
    - pathophysiology#Impaired NK Cell Differentiation
    supporting_outcome:
    - >-
      A selective NK developmental block at patient-equivalent GINS1 dosage,
      alongside growth restriction and neutropenia, would establish the
      lineage selectivity as a dose-dependent property of the replication
      defect rather than a human-specific observation.
    refuting_outcome:
    - >-
      Proportionate impairment across lymphoid lineages, or an NK compartment
      spared at patient-equivalent dosage, would argue the human NK
      selectivity depends on something absent from the mouse and would
      redirect the question toward human NK developmental biology.
  evidence:
  - reference: PMID:24244394
    reference_title: "Requirement of SLD5 for early embryogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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"
    explanation: >-
      Embryonic lethality of the null is the constraint that forces every model
      to be partial.
  - reference: PMID:24244394
    reference_title: "Requirement of SLD5 for early embryogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, heterozygous deletion of the SLD5 gene was found not to significantly affect bone marrow reconstitution."
    explanation: >-
      A negative result in the closest available heterozygous model,
      demonstrating that GINS dosage reduction does not generically reproduce
      the marrow phenotype.

- discussion_id: gins1_gene_disease_validity_consensus
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#GINS1
  prompt: >-
    Is the GINS1 gene-disease relationship established at ClinGen
    "Definitive"/"Strong" level, or only at "Moderate"/"Limited"?
  rationale: >-
    Nine published individuals, no ClinGen gene-disease validity assertion,
    and a 2026 review stating explicitly that variant interpretations remain
    conflicting. The functional rescue data are strong for the individual
    alleles, but allele-level functional evidence and gene-level validity are
    different claims. This entry records CAUSATIVE because the alternatives in
    the controlled vocabulary (DISPUTED, UNKNOWN) would misstate the evidence
    more badly, not because Definitive/Strong has been demonstrated.
  evidence:
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "interpretations of implicated variants remain conflicting, demonstrating a lack of consensus around the role of GINS1 in disease"
    explanation: >-
      States that the gene-disease relationship itself is not settled, which
      is what this gap is about.

phenotypes:
- category: Growth
  name: Intrauterine Growth Retardation
  description: >
    Present in all five reported patients and the most consistent
    non-immunological feature of the syndrome.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
    explanation: >
      Reports intrauterine growth retardation in all five patients.

- category: Growth
  name: Postnatal Growth Retardation
  description: >
    Four of the five patients also had postnatal growth retardation; P4 had
    intrauterine growth retardation with normal extrauterine growth, so this
    feature is not obligate.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four of the 5 patients also had postnatal growth retardation."
    explanation: >
      Reports postnatal growth retardation in four of five patients, which is
      why this is recorded as frequent but not obligate.

- category: Hematologic
  name: Chronic Neutropenia
  description: >
    Chronic, present in all five patients, and central in origin - the source
    attributes it to a bone marrow blockade. Described as mildly symptomatic,
    which is consistent with the patients' infection burden being weighted
    toward viruses rather than the pyogenic pattern of severe congenital
    neutropenia.
  phenotype_term:
    preferred_term: Chronic neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: CHRONIC
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
    explanation: >
      Reports chronic neutropenia in all five patients.

- category: Immunologic
  name: Natural Killer Cell Deficiency
  description: >
    The defining immunological lesion, present in all five patients and
    uniform across genotypes.
  phenotype_term:
    preferred_term: Reduced natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency."
    explanation: >
      Reports NK cell deficiency in all five patients.
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has overlapping features with the previously reported individuals, cementing growth retardation, neutropenia, and natural killer cell deficiency as core features."
    explanation: >
      Independent confirmation from the 2026 review that NK cell deficiency is
      a core rather than incidental feature across the published cohort.
  sequelae:
  - target: Recurrent Severe Viral Infection
    description: >
      Loss of NK effector function impairs control of herpesviruses in
      particular.

- category: Infectious
  name: Recurrent Severe Viral Infection
  description: >
    Reported episodes include prolonged acute CMV and varicella zoster
    infection, severe necrotizing varicella, recurrent herpes simplex, and
    adenovirus and RSV airway infections requiring hospitalisation. Documented
    bacterial infections also occurred, so the susceptibility is
    virus-weighted rather than virus-exclusive.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "infections with viruses but also some documented cases of bacterial infection"
    explanation: >
      Records that the reported infection burden comprised viral infections
      together with documented bacterial infections.
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "our proband, unlike the others, has no history of infections"
    explanation: >
      Recorded as REFUTE against recurrent infection being an obligate
      feature: at least one genetically confirmed individual has had no
      infections at all. This does not contradict the infections reported in
      the 2017 series - it establishes that infection burden is variable and
      that a normal infection history does not exclude the diagnosis.

- category: Immunologic
  name: Reduced CD8-Positive T Cell Count in Early Childhood
  description: >
    In the two patients tested during the first three years of life, blood
    T cell counts were low, especially CD8+ T cells. This is the observation
    that most supports the "combined" in the disease name, and it is
    age-limited: outside that window most patients had low or normal T and B
    lymphocyte numbers.
  phenotype_term:
    preferred_term: Decreased circulating CD8-positive T cell count
    term:
      id: HP:5210426
      label: Decreased total CD8+ T cell count
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the first 3 years of life, the two patients tested (P2 and P3) displayed low counts of blood T cells, especially CD8+ T cells."
    explanation: >
      Reports the reduced blood T cell counts, most marked for CD8+ T cells,
      in the two patients tested during the first three years of life.

- category: Craniofacial
  name: Mild Facial Dysmorphism
  description: >
    Reported in the patients alongside the growth retardation; not
    characterised into a recognisable gestalt in the source.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  severity: MILD
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dation (intra- and extrauterine) and mild facial dysmorphism, except patient 4 (P4; no extrauterine growth retardation)"
    explanation: >
      Records mild facial dysmorphism accompanying the growth retardation, and
      names P4 as the exception for extrauterine growth. The quote opens
      mid-word because the source PDF hyphenates "retar-|dation" across a line
      break.

- category: Hematologic
  name: Bone Marrow Dysplasia
  description: >
    Marrow examination showed reduced myelopoiesis with erythroid dysplasia in
    P3, slight dysgranulopoiesis in P4, and myelodysplasia in P5 - consistent
    with the maturation blockade being visible histologically, not only as a
    peripheral count.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myelodysplasia was documented in bone marrow analysis."
    explanation: >
      Documents marrow dysplasia in P5, the histological counterpart of the
      maturation blockade.

- category: Gastrointestinal
  name: Protein-Losing Enteropathy
  description: >
    Reported in P3, associated with recurrent severe diarrhoea, and
    consequential: the resulting low serum IgM and IgG prompted immunoglobulin
    replacement. Recorded as a single-patient finding.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diarrhea was associated with severe protein-losing enteropathy."
    explanation: >
      Records the association of P3's diarrhoea with severe protein-losing
      enteropathy.

- category: Ophthalmologic
  name: Glaucoma
  description: >
    Reported in more than one unrelated individual, including congenital
    unilateral glaucoma with secondary high myopia in the 2026 proband. The
    reviewing authors flag this as a possible expansion of the phenotype
    rather than an established core feature, and this entry follows that
    reading - it is recorded as an emerging association, not as part of the
    defining triad.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion"
    explanation: >
      Records glaucoma across more than one unrelated individual and the
      authors' own framing of it as a candidate phenotypic expansion.
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unilateral congenital glaucoma, causing secondary high myopia"
    explanation: >
      Describes the specific ocular phenotype in the 2026 proband.

experimental_models:
- name: Patient-derived fibroblasts with wild-type GINS1 rescue
  description: >
    The system that carries most of this entry's mechanistic weight. Primary
    fibroblasts from affected individuals reproduce the cellular phenotype -
    impaired GINS complex assembly, basal replication stress, impaired
    checkpoint signalling, defective cell cycle control and genomic
    instability - and re-expressing wild-type GINS1 reverses it. The rescue arm
    is what converts a set of correlated abnormalities in patient cells into a
    causal claim about GINS1.
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:28414293
  modeled_mechanisms:
  - target: Impaired GINS/CMG Replicative Helicase Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Patient cells carrying the actual disease genotypes show the assembly
      defect directly.
    limitations: >-
      Fibroblasts are not a haematopoietic lineage, so the model speaks to the
      general replication defect and to the growth arm, not to the marrow
      maturation blockade that defines the disease clinically. Cultured
      fibroblasts also proliferate under conditions unlike those of a
      differentiating progenitor in vivo.
    readouts:
    - name: GINS complex assembly
      target: Impaired GINS/CMG Replicative Helicase Assembly
      direction: DECREASED
      interpretation: Direct measurement of the molecular defect in patient cells.
      evidence:
      - reference: PMID:28414293
        reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "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."
        explanation: Reports impaired GINS complex assembly in patient fibroblasts.
    - name: Residual GINS1 activity
      target: Impaired GINS/CMG Replicative Helicase Assembly
      direction: DECREASED
      interpretation: >-
        Quantifies how much function the hypomorphic alleles retain, which is
        the disease-relevant quantity.
      evidence:
      - reference: PMID:28414293
        reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "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."
        explanation: Reports the residual activity range and its genotype dependence.
  - target: Defective Cell Cycle Control and Genomic Instability
    relationship: RESCUES
    fidelity: HIGH
    description: >
      Re-expression of wild-type GINS1 reverses the cellular phenotype, which
      is the causal test rather than an observation.
    limitations: >-
      Rescue is by transgenic overexpression rather than by correcting the
      endogenous alleles, so it establishes sufficiency of wild-type GINS1 but
      not the dose at which the phenotype would resolve.
    readouts:
    - name: Cell cycle control and genomic instability
      target: Defective Cell Cycle Control and Genomic Instability
      direction: RESTORED
      interpretation: The rescue arm; reversal on wild-type re-expression.
      evidence:
      - reference: PMID:28414293
        reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "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."
        explanation: >
          The same sentence reports the defects and their reversal by wild-type
          GINS1; the rescue clause is what this readout records.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Establishes patient fibroblasts with wild-type rescue as the system in
      which the cellular mechanism was demonstrated.

animal_models:
- name: Psf1 (Gins1) heterozygous mouse
  species: Mouse
  genotype: Psf1 heterozygous; Sld5 (Gins4) heterozygous and null comparators
  publication: PMID:24244394
  description: >
    Two things make this model informative, and they pull in opposite
    directions. Psf1 haploinsufficiency causes failure of acute bone marrow
    haematopoietic stem cell proliferation during reconstitution after 5-FU
    ablation - the closest animal counterpart to the human marrow phenotype.
    But heterozygous deletion of Sld5, another GINS subunit, does not
    significantly affect bone marrow reconstitution, so the marrow requirement
    is not a generic property of GINS dosage.
  modeled_mechanisms:
  - target: Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Reproduces a marrow proliferative failure from reduced Psf1 dosage, but
      only under regenerative stress and without the NK-lineage specificity
      that defines the human disease.
    limitations: >-
      The mouse phenotype is elicited by 5-FU ablation rather than arising at
      baseline, so it models regenerative demand rather than the steady-state
      maturation blockade seen in patients. NK cell numbers are not reported.
      Mouse Psf1 heterozygosity is also not the human genotype: patients are
      compound heterozygous for hypomorphic alleles retaining 3-16% activity,
      which is a different and lower dose than one intact allele.
    readouts:
    - name: Bone marrow HSC proliferation after 5-FU ablation
      target: Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
      direction: DECREASED
      interpretation: >-
        Marrow proliferative failure attributable to reduced Psf1 dosage.
      evidence:
      - reference: PMID:24244394
        reference_title: "Requirement of SLD5 for early embryogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We have previously reported that 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."
        explanation: Reports the marrow proliferative defect in Psf1 heterozygotes.
    - name: Bone marrow reconstitution in Sld5 heterozygotes
      target: Bone Marrow Maturation Blockade of Granulocyte and NK Lineages
      direction: UNCHANGED
      interpretation: >-
        A real negative result. Reduced dosage of a different GINS subunit does
        not reproduce the marrow phenotype, so the requirement is
        subunit-specific rather than a general consequence of GINS
        haploinsufficiency.
      evidence:
      - reference: PMID:24244394
        reference_title: "Requirement of SLD5 for early embryogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, heterozygous deletion of the SLD5 gene was found not to significantly affect bone marrow reconstitution."
        explanation: >
          Records the negative result for Sld5 heterozygotes, which is what
          makes the Psf1 finding subunit-specific.
  evidence:
  - reference: PMID:24244394
    reference_title: "Requirement of SLD5 for early embryogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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"
    explanation: >
      Establishes the embryonic lethality of complete GINS-subunit loss in
      mice, which is why every viable human genotype is hypomorphic.

genetic:
- name: GINS1
  gene_term:
    preferred_term: GINS1
    term:
      id: hgnc:28980
      label: GINS1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    `relationship_type: CAUSATIVE` is recorded here with a caveat. The
    schema's own definition of CAUSATIVE corresponds to ClinGen "Definitive"
    or "Strong" gene-disease validity, and the 2026 review states that
    interpretations of implicated variants remain conflicting and that there
    is a lack of consensus around the role of GINS1 in disease. The
    justification for CAUSATIVE rather than DISPUTED or UNKNOWN is the
    functional evidence: patient-fibroblast phenotypes rescued by wild-type
    GINS1, which is ACMG PS3-level support. The honest label would be
    somewhere around ClinGen "Moderate" or "Limited", and
    `GeneDiseaseRelationshipEnum` has no value between CAUSATIVE
    (Definitive/Strong) and DISPUTED (Disputed/Refuted) to carry that.
  notes: >
    GINS1 (also known as PSF1) encodes one of the four subunits of the GINS
    complex, which together with CDC45 and the MCM2-7 hexamer forms the CMG
    replicative helicase. All five reported patients are compound
    heterozygotes. Complete biallelic loss is not represented among patients
    and is not expected to be: homozygous null mutations of GINS
    component-encoding genes are embryonic lethal in mice. The measured
    residual activity of 3-16% is therefore the disease-relevant quantity, and
    it behaves differently toward the two clinical arms - grading growth
    retardation and the cellular phenotype, but not the immune phenotype.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
    explanation: >
      Establishes GINS1 as the causal gene and the compound heterozygous
      allelic architecture.
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Quantifies the hypomorphic residual activity and its genotype
      dependence.

variants:
- name: GINS1 c.247C>T (p.Arg83Cys)
  description: >-
    Missense variant in exon 4 replacing arginine with cysteine at position 83.
    Predicted damaging with a CADD score of 35 against a GINS1-specific
    mutation significance cutoff of 16.5. Both missense alleles are present in
    ExAC at low minor allele frequencies, so unlike the 5' UTR alleles they
    are not absent from population reference data - consistent with
    hypomorphic rather than null alleles.
  gene:
    preferred_term: GINS1
    term:
      id: hgnc:28980
      label: GINS1
  type: SNV
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nine with a cysteine residue in position 83 (p.R83C), a change pre- dicted to be damaging (CADD score 35"
    explanation: >-
      Records the p.R83C substitution and its CADD score. The quote opens and
      closes mid-word because the source PDF hyphenates "argi-|nine" and
      "pre-|dicted" across line breaks.
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Both the R83C and C152Y substitutions were reported in the Exome Aggregation Consortium (ExAC) database"
    explanation: >-
      Documents that both missense alleles appear in ExAC, the population
      reference dataset available at the time of the founding report.
  - reference: PMID:41689265
    reference_title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This variant is observed at an allele frequency of 0.066% in population controls in the Genome Aggregation Database (gnomAD), with a maximum allele frequency of 0.4% in the European (Finnish) population."
    explanation: >-
      Updated population frequency from gnomAD. The 0.4% Finnish maximum is
      high for a recessive disease allele and is the main reason this variant
      is best read as hypomorphic rather than null - a true null at that
      frequency would be expected to produce homozygotes, which are not
      observed.

- name: GINS1 c.455G>A (p.Cys152Tyr)
  description: >-
    Missense variant in exon 6 replacing cysteine with tyrosine at position
    152, predicted damaging with a CADD score of 32.
  gene:
    preferred_term: GINS1
    term:
      id: hgnc:28980
      label: GINS1
  type: SNV
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a c.455G>A substitution in exon 6 leading to the replacement of a cysteine with a tyrosine residue in position 152 (p.C152Y)"
    explanation: >-
      Records the c.455G>A change and the residue it substitutes.

- name: GINS1 5' UTR substitutions at positions -48 and -60
  description: >-
    Two non-coding substitutions in the 5' untranslated region, at positions
    -48 and -60 relative to the ATG. These are the regulatory arm of the
    allelic spectrum and are the reason the disease is expressed as reduced
    rather than absent GINS1: a promoter/UTR-level reduction in expression
    leaves residual protein where a coding null would not.
  gene:
    preferred_term: GINS1
    term:
      id: hgnc:28980
      label: GINS1
  type: SNV
  regulatory_category: LOE
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and p.C152Y) and two 5\u2032 UTR nucleotide substitutions (at posi- tions -48 and -60 relative to the ATG"
    explanation: >-
      Records the two 5' UTR substitutions and their positions relative to the
      ATG. The quote preserves the source's "posi-|tions" hyphen break.

diagnosis:
- name: Lymphocyte Subset Immunophenotyping
  description: >
    Flow cytometric enumeration of NK cells is the entry point: a profoundly
    reduced NK count in a child with intrauterine growth retardation and
    chronic neutropenia is the syndrome's recognisable signature, and the
    pairing is the discriminating feature.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      The unusual pairing of neutropenia with NK cell deficiency is what makes
      the combined immunophenotype diagnostically informative.

- name: Bone Marrow Examination
  description: >
    Marrow analysis distinguishes a central maturation blockade from
    peripheral consumption and shows the dysplastic changes reported in
    several patients.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myelodysplasia was documented in bone marrow analysis."
    explanation: >
      Marrow examination is what demonstrated the dysplastic changes underlying
      the peripheral cytopenias.

- name: Molecular Genetic Testing of GINS1
  description: >
    Confirmatory. Biallelic GINS1 variants establish the diagnosis; because
    complete loss of function is lethal, a plausible genotype must retain
    residual activity on at least one allele.
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients."
    explanation: >
      Biallelic GINS1 variants are the molecular diagnostic criterion.

treatments:
- name: Granulocyte Colony-Stimulating Factor
  description: >
    Used in P5 for the chronic neutropenia. The source records the treatment,
    not a measured response, so this is documented management rather than
    demonstrated efficacy. Modality is `OTHER` rather than
    `PROTEIN_REPLACEMENT`: recombinant G-CSF is given to stimulate
    granulopoiesis pharmacologically, and these patients are not G-CSF
    deficient - the lesion is downstream of the cytokine.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: granulocyte colony-stimulating factor
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient P5 was treated by G-CSF."
    explanation: >
      Documents G-CSF use in one reported patient. No response measure is
      reported, so no efficacy claim is made here.

- name: Immunoglobulin Replacement Therapy
  description: >
    Initiated in P3 for low serum IgM and IgG driven by protein-losing
    enteropathy, together with antibiotic prophylaxis. The reported effect -
    a large reduction in airway infection frequency - is attributed to the
    combination, not to either component alone.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immunoglobulin replacement and antibiotic prophylaxis were initiated, greatly decreasing the frequency of airway infections."
    explanation: >
      Records the initiation of immunoglobulin replacement together with
      antibiotic prophylaxis, and the reported effect. The effect is attributed
      to the combination, not to either component alone.

- name: Antimicrobial Prophylaxis
  description: >
    Trimethoprim/sulfamethoxazole prophylaxis was given to P4 from age 15 to
    24 years; antibiotic prophylaxis was also part of P3's regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She received prophylactic antibiotic treatment (trimethoprim/sulfamethoxazole) from 15 to 24 years of age."
    explanation: >
      Documents the specific agents and the duration of antimicrobial
      prophylaxis in P4, which is what the bound CHEBI agents rest on.

- name: Enteral and Parenteral Nutritional Support
  description: >
    Attempted for the growth failure, and notable for failing. P3's growth
    retardation did not respond to enteral feeding support including
    percutaneous endoscopic gastrostomy, or to parenteral feeding. Recorded
    because the negative result is mechanistically informative: it argues the
    growth arm is a cell-intrinsic proliferative limit rather than a
    nutritional deficit.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:28414293
    reference_title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The growth retardation was extremely pronounced and did not respond to enteral feeding support including percutaneous endoscopic gastrostomy (PEG) feed- ing or to parenteral feeding."
    explanation: >
      Reports failure of nutritional support, including PEG and parenteral
      feeding, to correct the growth retardation. Recorded as REFUTE because it
      is a negative result about this intervention, and it is mechanistically
      informative: the growth arm is a cell-intrinsic proliferative limit, not
      a nutritional one. The quote preserves the source's "feed- ing" hyphen
      break.

references:
- reference: PMID:28414293
  title: "Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency."
- reference: PMID:36809597
  title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
- reference: PMID:41689265
  title: "Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature."
📚

References & Deep Research

References

3
PMID:28414293
Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.
No top-level findings curated for this source.
PMID:36809597
Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity.
No top-level findings curated for this source.
PMID:41689265
Expanding Phenotype of GINS1 Deficiency: A Case Report and Review of the Literature.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
Combined Immunodeficiency Due to GINS1 Deficiency — Comprehensive Disease Characteristics Report
openscientist-autonomous 8 citations 2026-08-30T18:46:47.961696

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:

Variant cDNA Protein gnomAD exome AF ClinVar
5′UTR c.-48C>G p.? 3.9×10⁻⁶ (5 alleles) ultrarare
Missense c.247C>T p.Arg83Cys 6.6×10⁻⁴ (951 alleles) conflicting classifications
Missense c.455G>A p.Cys152Tyr — Likely pathogenic

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

Resource Identifier
MONDO MONDO:0044725 ("combined immunodeficiency due to GINS1 deficiency")
OMIM phenotype #617827 (Immunodeficiency 55, IMD55)
OMIM gene 610608 (GINS1*)
HGNC HGNC:28980
NCBI Gene 9837
Ensembl ENSG00000101003
UniProt Q14691
Cytoband 20p11.21
Orphanet "Combined immunodeficiency due to GINS1 deficiency"
MeSH No dedicated descriptor (indexed under Severe Combined Immunodeficiency / Primary Immunodeficiency Diseases)

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

Phenotype Type HPO Onset Frequency Severity/course
Intrauterine growth retardation clinical sign HP:0001511 prenatal 100% (5/5, 9/9) severe, tracks residual activity
Postnatal growth retardation / short stature clinical sign HP:0004322 infancy ~80% (4/5) variable
Chronic neutropenia lab abnormality HP:0001875 congenital core (all) chronic, "mildly symptomatic"
NK-cell deficiency lab abnormality HP:0040218 congenital core (all) persistent
Distinctive facial features physical HP:0001999 congenital subset emerging
Glaucoma clinical sign HP:0000501 early childhood multiple unrelated emerging
Viral susceptibility symptom — variable variable (some none) variable

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:

Feature GINS1 deficiency MCM4 deficiency CDC45 deficiency
Gene / complex role GINS subunit (CMG) MCM2-7 helicase core (CMG) CMG activator/component
Inheritance Autosomal recessive Autosomal recessive Autosomal dominant (allelic-expression bias)
Growth retardation Yes (IUGR + postnatal) Yes (short stature) Variable
NK-cell deficiency Yes (core) Yes (selective, CD56dim) Yes (variable)
Neutropenia Yes (core) Not prominent Variable
Adrenal insufficiency No Yes (characteristic) No
Genomic instability Yes Yes Yes
Key refs 28414293 22354167 / 22354170 41867723

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

PMID Title (abbrev.) Role in this report
28414293 Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency Landmark defining paper. Establishes the disease, core triad, autosomal-recessive inheritance, hypomorphic mechanism (3–16% residual activity), and the fibroblast replication-stress phenotype. Supports Findings 1, 2, 5, 7, 8.
41689265 Expanding Phenotype of GINS1 Deficiency: A Case Report and Review Phenotype expansion. New patient with dysmorphism and glaucoma, variant details (c.-48C>G; p.Arg83Cys), and confirmation of the core triad across 9 individuals. Supports Findings 3, 5.
35038632 Increased contribution of DNA polymerase delta to leading-strand replication with an impaired CMG helicase Defines GINS role within the CMG helicase. Supports Finding 2.
24244394 Requirement of SLD5 for early embryogenesis Mouse model: GINS-subunit knockout is embryonic lethal; PSF1 dosage limits HSC proliferation. Supports Finding 4.
22354167 Partial MCM4 deficiency…growth retardation, adrenal insufficiency, and NK cell deficiency Analogous helicasopathy and primary differential diagnosis. Supports Finding 4.
22354170 MCM4 mutation causes adrenal failure, short stature, and NK cell deficiency Corroborates MCM4 phenotype and genomic-instability/replicative-helicase theme. Context for Finding 4.
24135998 Inborn errors of the development of human natural killer cells Frames NK-cell deficiencies including replicative-helicase causes. Context for Finding 4.
40577589, 20709026 Drosophila CMG/Sld5 studies Show identical mitotic defects on knockdown of any GINS subunit; genomic-integrity role. Context for Finding 4.
41867723 Autosomal dominant CDC45 deficiency… Related CMG-component immune disease (NK reduction). Comparative context.
31815930, 33322195, 37481989 Yeast CMG/GINS mechanism papers Mechanistic support for replication-stress/genomic-instability consequences of impaired GINS/CMG. Context for Finding 2.

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

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 17
Quoted claims found in source 16
Quoted claims not found in source 1
References weighed for topical relevance 13
On topic 7
Off topic 0

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

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 24
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 8
Terms named correctly 1
Terms named as a different term 7

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"