Immunodeficiency 122

Mendelian MONDO:0971151 Pathograph 29 Show in embeddings browser Combined Immunodeficiency Inborn Errors of Immunity

IMD122 is the syndromic combined immunodeficiency caused by biallelic variants in POLD3, an accessory subunit of DNA polymerase delta. Two unrelated patients are published, each homozygous for a different missense variant: a Lebanese child of a consanguineous family with a syndromic SCID, neurodevelopmental delay and hearing loss, and a boy of Moroccan descent who presented as Omenn syndrome and died at four. Three further siblings of the first patient died in early childhood of a comparable illness but were not genotyped, so the genetically confirmed count is two. The mechanism is the same proliferation defect that underlies the sibling polymerase-delta immunodeficiencies POLD1 (IMD120) and POLD2. Polymerase delta is a heterotetramer: POLD1 carries the catalytic activities, POLD2 is the scaffold, and POLD3 and POLD4 regulate the activity and stability of the complex and establish its contacts, with POLD3 in particular mediating the interaction with PCNA that the holoenzyme needs for processivity. A hypomorphic accessory subunit lowers the enzyme's output, which restricts how many cells can enter and complete S phase. Lymphocytes expand fastest on demand, so they fail first, and the disease presents as a T-cell deficiency. The two alleles reach that output by different routes, which is the useful part of having two patients. p.Ile10Thr sits in the POLD2-binding region and abolishes expression of POLD3 along with POLD1 and POLD2 — the destabilisation route, the same one the POLD1 CysB allele takes. p.Lys373Thr sits in a positively charged interdomain region thought to aid DNA binding, and leaves the expression of all three subunits intact while impairing function — the reduced-activity route. Different lesions, convergent phenotype, which is the argument that the disease follows from reduced polymerase delta output rather than from a property of one allele. Unlike the POLD1 patients, where DNA repair after genotoxic stress was reported normal, the Omenn patient's fibroblasts showed both a marked defect in S-phase entry and an increased number of double-strand-break-associated foci, so replicative stress and DNA damage are directly documented here. The cell-cycle defect was rescued by re-expressing wild-type POLD3, which establishes the direction of causation. Clinically it presents in infancy with recurrent infection, profound depletion of naive T cells, a restricted T-cell receptor repertoire and defective early TCR recombination. The Omenn patient had the full dysregulation picture — erythroderma, alopecia, eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly and an absent thymus — and received a haematopoietic stem cell transplant at six months. The Lebanese patient had low naive T cells with preserved B-cell numbers, sensorineural hearing loss and developmental delay. Both carry syndromic non-immune features, which is why the entry is classified as a combined immunodeficiency with syndromic features.

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1
Inheritance
9
Pathophys.
18
Phenotypes
2
Gaps
29
Pathograph
1
Genes
2
Medical Actions
3
References
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
combined immunodeficiency with syndromic features
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic in both families. Both patients are homozygous, each the child of a consanguineous union, with the variant segregating with autosomal recessive inheritance and confirmed by Sanger sequencing. Heterozygous carriers are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The identified variant in the POLD3 gene (NM_006591) was a homozygous variant in exon 10 (c.1118A > C) with a CADD score of 25 that segregated with autosomal recessive inheritance, as confirmed by Sanger sequencing"
Homozygosity and segregation consistent with recessive inheritance in the Omenn patient, confirmed by a second method.
PMID:37030525 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
The second homozygous genotype in a consanguineous family, which establishes recessive inheritance in a second independent kindred.
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Discussions and Knowledge Gaps

2
Why does one POLD3 genotype present as florid Omenn syndrome with documented DNA damage while the other presents as a milder syndromic CID — is it the allele, the degree of residual function, or something else?
OPEN QUESTION OPEN imd122_omenn_vs_cid_spectrum
Attached to
pathophysiology#Destabilisation of the Polymerase Delta Complex pathophysiology#Impaired Polymerase Delta Function with Intact Complex pathophysiology#Replication-Associated DNA Damage
The two patients differ along two axes at once, which is exactly what makes the question hard. The Omenn patient (p.Lys373Thr) has normal subunit expression but impaired function, a marked S-phase-entry defect and increased double-strand-break foci, and the full dysregulation picture. The Lebanese patient (p.Ile10Thr) has abolished subunit expression — a seemingly more severe molecular lesion — but a milder clinical picture of syndromic CID with preserved B-cell numbers and no reported Omenn features. So the more complete loss of protein does not map to the more severe clinical picture, which argues the phenotype is set by residual holoenzyme output and by which downstream processes it limits rather than by subunit abundance. Distinguishing the possibilities needs the missing measurements: cell-cycle and DNA-damage assays were done only in the Omenn patient, so there is no functional comparison of the two alleles in the same assay.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components."
The key asymmetry: the clinically more severe (Omenn) patient has normal subunit expression, so the severity cannot be read off protein abundance.
Are the developmental and sensorineural features of POLD3 deficiency a direct consequence of reduced polymerase delta in dividing non-haematopoietic tissue, as the mouse replication-stress phenotype would suggest, or are they confounded by infection and transplant course in the two human patients?
HUMAN MODEL MISMATCH OPEN imd122_syndromic_attribution
Attached to
pathophysiology#Syndromic Developmental and Sensorineural Features phenotypes#Sensorineural Hearing Loss phenotypes#Global Developmental Delay
The mouse supplies a clean mechanistic prediction: Pold3 loss causes embryonic replication stress with brain-preferential phenotypes reminiscent of microcephaly syndromes, so a hypomorphic human should show developmental effects. The human data cannot confirm it. No non-haematopoietic tissue was examined in either patient; the Lebanese patient's hearing loss and developmental delay are reported without mechanism; and the Omenn patient's neurodevelopmental course is confounded by his transplant, conditioning and fatal neurological regression. The model predicts a direct developmental effect that the human evidence can neither establish nor exclude — classified HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the model evidence exists and the open question is its translational validity, not the absence of any evidence.
Show evidence (1 reference)
PMID:27524497 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"POLD3 is essential for mouse development and is also required for viability in adult animals"
The model evidence that a POLD3 deficit affects development, which is what makes this a model-to-human validity question rather than an absence of evidence.
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Pathophysiology

9
Biallelic Hypomorphic POLD3 Variants
Mechanism confidence: Established
Two homozygous missense genotypes are published, one per family. The Lebanese patient is homozygous for c.29T>C, p.Ile10Thr, in the POLD2-binding region of POLD3; the Omenn patient is homozygous for c.1118A>C, p.Lys373Thr, in a positively charged interdomain region thought to aid polymerase activity and DNA binding. No null allele appears, and none is expected to: in mice POLD3 is essential for development and for viability in adult animals, and even heterozygous loss is haploinsufficient for stabilising the complex. A viable patient's alleles are hypomorphic by construction.
POLD3 hgnc:20932 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POLD3 (hgnc:20932). hgnc:20932 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context POLD3 hgnc:20932 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns POLD3 (hgnc:20932). hgnc:20932 is a gene from the HUGO Gene Nomenclature Committee. allele_type: homozygous missense in each family — p.Ile10Thr in one, p.Lys373Thr in the other variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION, and the reasoning is not a hedge: complete POLD3 loss is embryonic lethal in mice and POLD3 is haploinsufficient even in the heterozygous state, so a viable patient's alleles must retain some function. One allele nonetheless abolishes detectable protein — the hypomorphism is at the level of the holoenzyme's residual output, not necessarily of each subunit's expression.
Downstream
Destabilisation of the Polymerase Delta Complex The p.Ile10Thr route. The substitution lies in the POLD2-binding region and abolishes the steady-state amount of POLD3, POLD1 and POLD2 together — the complex cannot assemble, so all three measured subunits drop.
Impaired Polymerase Delta Function with Intact Complex The p.Lys373Thr route. Expression of all three subunits is preserved, so the complex assembles, but function is impaired — the distinct second mechanism reaching the same output.
Show evidence (2 references)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome."
The Omenn patient's genotype, found and reported by this study.
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"WES identified a homozygous variant (c.29 T > C; p.I10T) in the POLD2 binding region of POLD3, and patient cells showed no expression of POLD3, POLD1, or POLD2."
The Lebanese patient's genotype and the subunit location, quoted from this paper's summary of the concurrently published Mehawej case so both alleles are described from one source.
Destabilisation of the Polymerase Delta Complex
Mechanism confidence: Established
POLD3 stabilises the POLD1-POLD2 interaction, so a variant in its POLD2-binding region does not inactivate one subunit, it lowers the amount of assembled enzyme. In the mouse, deleting Pold3 destabilises every member of the complex, which is the model for why one subunit's loss drags the others down.
POLD3 hgnc:20932 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POLD3 (hgnc:20932). hgnc:20932 is a gene from the HUGO Gene Nomenclature Committee.
DNA polymerase delta complex GO:0043625 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased DNA polymerase delta complex, annotated with delta DNA polymerase complex (GO:0043625). GO:0043625 is a cellular component from the Gene Ontology.
Downstream
Impaired DNA Replication and S-Phase Entry
Show evidence (1 reference)
PMID:27524497 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"we show that Pold3 deletion destabilizes all members of the Polδ complex, explaining its major role in DNA replication and the severe impact of its deficiency"
The mechanism by which loss of one subunit lowers the whole complex, shown in the mouse. Graded INDIRECT and MODEL_ORGANISM because it is the murine result applied to the human destabilising allele, whose own subunit loss is the node's human evidence.
Impaired Polymerase Delta Function with Intact Complex
Mechanism confidence: Established
The second route to the same deficit. p.Lys373Thr leaves the complex assembled and all three subunits expressed at normal levels, but lies in a positively charged region implicated in DNA binding and polymerase processivity, so it compromises function rather than amount. The two families therefore differ in biochemistry and agree in phenotype, which is the argument that the disease follows from reduced polymerase delta output rather than from a property of one allele.
POLD3 hgnc:20932 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POLD3 (hgnc:20932). hgnc:20932 is a gene from the HUGO Gene Nomenclature Committee.
DNA-directed DNA polymerase activity GO:0003887 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-directed DNA polymerase activity (GO:0003887). GO:0003887 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired DNA Replication and S-Phase Entry
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The cell cycle defect was rescued by transduction with WT POLD3."
Re-expressing wild-type POLD3 corrected the cellular phenotype, which establishes that the variant impairs POLD3 function and that the function is causal for the defect downstream.
Impaired DNA Replication and S-Phase Entry
Mechanism confidence: Established
POLD3 mediates the complex's interaction with PCNA, which the holoenzyme needs for activity and processivity, so less functional polymerase delta means fewer cells begin and complete DNA synthesis. The Omenn patient's fibroblasts showed a marked defect in S-phase entry and reduced proliferation over a week in culture, and the defect was at the entry to S phase rather than in elongation.
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 cell cycle GO:0007049 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell cycle (GO:0007049). GO:0007049 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Replication-Associated DNA Damage
Impaired T Cell Development and Proliferation
Show evidence (2 references)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT In Vitro
"it appears that the reduced proliferation in patient fibroblasts is caused by cellular arrest at the entry to the S phase"
The localisation of the defect to S-phase entry in the patient's cells.
PMID:38099988 SUPPORT INDIRECT BACKGROUND In Vitro
"POLD3 mediates interaction with proliferating cell nuclear antigen (PCNA), which is essential for PolD activity and processivity"
The specific role of POLD3 — the PCNA interaction — that a POLD3 lesion disrupts. Quoted from this paper's introduction, hence quote_role BACKGROUND; it is the node's mechanistic premise rather than a measurement.
Replication-Associated DNA Damage
Mechanism confidence: Established
Unresolved replicative stress produces double-strand breaks. The Omenn patient's fibroblasts carried an increased number of double-strand-break-associated foci despite normal subunit expression, which is the direct evidence of DNA damage that the POLD1 patients lacked. This is the branch that pushes the phenotype towards the DNA-damage end of the polymerase-delta spectrum, consistent with the Omenn rather than the milder CID presentation.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired T Cell Development and Proliferation
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components."
The replication-associated DNA damage measured in the patient's cells.
Impaired T Cell Development and Proliferation
Mechanism confidence: Established
Antigen-receptor recombination and clonal expansion both require heightened, accurate DNA replication, so a replication-limited progenitor pool fails at T-cell development first. The Omenn patient had a defect in the early stages of TCR recombination, severely reduced naive T cells and a restricted repertoire; the Lebanese patient had low naive T cells with preserved B-cell numbers. The B-cell compartment is comparatively spared, which is why the defect presents as T-cell rather than purely combined at the cellular level.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
T cell receptor V(D)J recombination GO:0033153 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor V(D)J recombination (GO:0033153). GO:0033153 is a biological process from the Gene Ontology. ↓ DECREASED T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased CD8+ T Cell Proportion
Decreased Naive T Cell Proportion
Restricted T Cell Receptor Repertoire
Oligoclonal T Cell Expansion
Severe Combined Immunodeficiency
Recurrent Infections
Thymic Aplasia Drawn tentatively: the Omenn patient had no demonstrable thymus on imaging, which in a proliferation-limited T-cell defect is consistent with failed thymic cellularity, but no thymic histology was obtained and the edge is an inference from the imaging rather than a measured step.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination."
The three joined features — naive T-cell loss, restricted repertoire and defective early recombination — that make this a developmental T-cell defect.
Oligoclonal T Cell Expansion
Mechanism confidence: Established
A repertoire that is both small and oligoclonal. In the Omenn patient the TCR V-beta repertoire was oligoclonal and TRB diversity was reduced to about a third of a healthy control, while B-cell IgH diversity was comparatively preserved — the same asymmetry seen in the POLD1 sibling disease. An oligoclonal, autoreactive T-cell expansion on a background of profound T-cell deficiency is the immunological basis of the Omenn presentation.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
Downstream
Omenn-Type Immune Dysregulation Oligoclonal, poorly selected T cells drive the erythroderma, eosinophilia and raised IgE that define the Omenn phenotype. The step is the standard reading of Omenn immunobiology applied to this patient's measured repertoire rather than a finding specific to POLD3.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
The oligoclonal repertoire measured in the Omenn patient, alongside the IgE and eosinophilia that accompany it.
Omenn-Type Immune Dysregulation
Mechanism confidence: Provisional
The dysregulation syndrome seen in the Omenn patient: erythroderma, alopecia, generalised lymphadenopathy, hepatosplenomegaly, eosinophilia and elevated IgE. Graded PROVISIONAL because it rests on one patient; the Lebanese patient did not have the Omenn picture, so whether Omenn-type dysregulation is a feature of POLD3 deficiency or of this particular allele and course is not settled.
Downstream
Erythroderma
Alopecia
Eosinophilia
Elevated Serum IgE
Hepatosplenomegaly
Lymphadenopathy
Increased Natural Killer Cell Count Drawn tentatively. The raised NK proportion was measured alongside the Omenn picture before transplant, but the source offers no mechanism for it, and a relative NK excess can follow from a contracted T-cell compartment rather than from NK expansion as such.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
The clinical dysregulation features in the Omenn patient.
Syndromic Developmental and Sensorineural Features
Mechanism confidence: Hypothetical
Neurodevelopmental delay in both patients, sensorineural hearing loss in the Lebanese patient, and growth retardation with facial dysmorphism in the Omenn patient. The mechanism is assumed rather than shown: polymerase delta is required wherever cells divide, so a general replication restriction should affect development — and the mouse models the point, with replication-stress features reminiscent of microcephaly syndromes. No non-haematopoietic tissue was examined in either patient, and the Omenn patient's post-transplant neurological regression confounds the developmental attribution, so the node is graded HYPOTHETICAL.
Downstream
Sensorineural Hearing Loss
Global Developmental Delay
Growth Delay
Facial Dysmorphism
Show evidence (1 reference)
PMID:37030525 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
That the developmental and sensorineural features are part of the described syndrome. It supports their inclusion in the entity, not the replication mechanism this node proposes for them, which is why the node is HYPOTHETICAL.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 122 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Blood 7
Decreased CD8+ T Cell Proportion OCCASIONAL Decreased total CD8+ T cell proportion HP:0005415 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased CD8+ T cell proportion, annotated with Decreased total CD8+ T cell proportion (HP:0005415). HP:0005415 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient). Bound to the proportion term rather than HP:5210425 (Decreased total CD8+ T cell number) because the source reports a percentage, not an absolute count. HPO defines the proportion as a percentage of CD3+ T cells; the source table does not state its denominator, and its CD3+ value of 58% suggests a percentage of lymphocytes. Either way the CD8+ fraction is low while CD3+ and CD4+ are in range. Subset counts for the Lebanese patient are not reported beyond low naive T cells, so this is not recorded for him.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"CD8 + (%) | 3 | 12–28"
Table 1 row for the Omenn patient before transplant: 3% CD8+ cells against a 12-28% reference range.
Decreased Naive T Cell Proportion VERY_FREQUENT HP:0031397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased naive T cell proportion (HP:0031397). HP:0031397 is a phenotype from the Human Phenotype Ontology.
2 of 2 genotyped patients.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had low naïve T cells but normal B cell counts, and he had normal IgG and IgM but partially deficient IgA."
The naive-T-cell loss with preserved B-cell numbers in the Lebanese patient, quoted from this paper's summary of that case.
Restricted T Cell Receptor Repertoire OCCASIONAL Abnormal TCR repertoire HP:0025845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligoclonal, restricted T-cell receptor repertoire, annotated with Abnormal TCR repertoire (HP:0025845). HP:0025845 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (measured in the Omenn patient). Bound to the general abnormal-TCR-repertoire term because HPO has no term for a restricted or oligoclonal repertoire specifically; the restriction is carried in preferred_term and description.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Prior to HSCT, the patient displayed severely reduced levels of naïve T cells and a restricted TCR Vβ repertoire"
The restricted TCR V-beta repertoire measured in the Omenn patient before transplant.
Eosinophilia OCCASIONAL Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilia, annotated with Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
The eosinophilia in the Omenn patient.
Elevated Serum IgE OCCASIONAL Increased circulating IgE concentration HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum IgE, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
The elevated IgE in the Omenn patient.
Increased Natural Killer Cell Count OCCASIONAL Increased total natural killer cell count HP:6000677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased natural killer cell proportion, annotated with Increased total natural killer cell count (HP:6000677). HP:6000677 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient). The source reports a percentage of lymphocytes, not an absolute count; HPO has no NK-proportion term, so the count term is bound and the measure is carried in preferred_term and description.
Show evidence (2 references)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"NK (%) | 32 | 4–18"
Table 1 row for the Omenn patient before transplant, above the reference range.
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Immunological analysis prior to HSCT showed severely reduced naiïve CD4+ and CD8+ cells, low memory B cells, and high NK cells"
The authors' own reading of the subset analysis, naming the NK excess.
Decreased Circulating IgA OCCASIONAL Decreased circulating IgA concentration HP:0002720 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Partial IgA deficiency, annotated with Decreased circulating IgA concentration (HP:0002720). HP:0002720 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Lebanese patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had low naïve T cells but normal B cell counts, and he had normal IgG and IgM but partially deficient IgA."
The Lebanese patient's humoral picture, quoted from this paper's summary of that case.
Cardiovascular 3
Thymic Aplasia OCCASIONAL Aplasia of the thymus HP:0005359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thymus not visualised on imaging, annotated with Aplasia of the thymus (HP:0005359). HP:0005359 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Chest X-ray and ultrasound failed to show a thymus."
The absent thymus on imaging in the Omenn patient.
Hepatosplenomegaly OCCASIONAL HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
The hepatosplenomegaly in the Omenn patient.
Lymphadenopathy OCCASIONAL HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized lymphadenopathy, annotated with Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
The lymphadenopathy in the Omenn patient.
Ear 1
Sensorineural Hearing Loss OCCASIONAL Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Lebanese patient). The Omenn patient's hearing is not reported, so this is recorded as present in one rather than variable across both.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Furthermore, the patient had sensorineural hearing loss and developmental delay."
The hearing loss and developmental delay in the Lebanese patient, quoted from this paper's summary of that case.
Head and Neck 1
Facial Dysmorphism OCCASIONAL Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient). Facial features are not reported for the Lebanese patient.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
The facial dysmorphism in the Omenn patient at three years.
Immune 3
Severe Combined Immunodeficiency VERY_FREQUENT HP:0004430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe combined immunodeficiency (HP:0004430). HP:0004430 is a phenotype from the Human Phenotype Ontology.
2 of 2 genotyped patients.
Show evidence (1 reference)
PMID:37030525 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Our findings implicate POLD3 deficiency as a novel cause of syndromic SCID."
The entity's defining immune phenotype, stated as the paper's conclusion.
Recurrent Infections VERY_FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719), qualified as temporality recurrent. HP:0002719 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
2 of 2 genotyped patients.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The index case presented at 4y with a history of recurrent infections from 7 months. His siblings had died at ages 3, 5, and 5 years."
The recurrent-infection history in the Lebanese patient, with the three early-childhood sibling deaths that frame the family's burden. Quoted from this paper's summary of the Mehawej case.
Erythroderma OCCASIONAL HP:0001019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythroderma (HP:0001019). HP:0001019 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
The erythroderma in the Omenn patient.
Integument 1
Alopecia OCCASIONAL HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient).
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
The alopecia in the Omenn patient.
Nervous System 1
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
2 of 2 genotyped patients.
Show evidence (2 references)
PMID:37030525 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
The neurodevelopmental delay named in the Lebanese patient's presentation.
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
The developmental delay in the Omenn patient at three years, the second of the two patients.
Growth 1
Growth Delay OCCASIONAL HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
1 of 2 genotyped patients (the Omenn patient). His post-transplant course confounds the attribution, since conditioning and chronic illness also retard growth.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
The growth retardation in the Omenn patient at three years.
🧬

Genetic Associations

1
POLD3
Gene: POLD3 hgnc:20932 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POLD3 (hgnc:20932). hgnc:20932 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT BACKGROUND In Vitro
"POLD3, with POLD2 and POLD4, regulate the activity of POLD1, the activity and stability of PolD, and establish protein–protein interactions"
POLD3's role in the complex, quoted from this paper's introduction (hence quote_role BACKGROUND) as the established biology a POLD3 lesion disrupts.
💊

Medical Actions

2
Haematopoietic Stem Cell Transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The only reported route to correcting the immune defect. The Omenn patient received HSCT at six months from a 10/10 matched unrelated donor after conditioning, with a stem-cell boost for low chimerism. It replaces the haematopoietic compartment with cells carrying two working POLD3 alleles, but does nothing for the non-haematopoietic features — this patient's neurological regression continued and he died at four. Whether a defect in the replicative polymerase raises conditioning-related toxicity, as it is feared to in the POLD1 sibling disease, is not addressed in either report.
Mechanism Target:
Impaired T Cell Development and Proliferation — Donor cells with functional POLD3 remove the proliferation ceiling in the lineage where it matters. It leaves the developmental and sensorineural features untouched.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He underwent hematopoietic stem cell transplantation (HSCT) at 6 months with a 10/10 matched unrelated donor, following conditioning with alemtuzumab, treosulfan, and fiudarabine, with the need for a stem cell boost ~ 8 months later because of chimerism < 20%."
The transplant and its course in the Omenn patient. The source's "fiudarabine" is an OCR artefact for fludarabine, quoted verbatim as the snippet must match the cache.
Immunosuppression for Omenn Syndrome
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: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest. cyclosporine CHEBI:4031 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclosporine, annotated with cyclosporin A (CHEBI:4031). CHEBI:4031 is a therapeutic agent from Chemical Entities of Biological Interest. alemtuzumab NCIT:C1681 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses alemtuzumab (NCIT:C1681). NCIT:C1681 is a therapeutic agent from the NCI Thesaurus.
Before transplant the Omenn patient received steroids, cyclosporine and alemtuzumab for the Omenn picture. The aim is to suppress the oligoclonal, activated T cells driving the erythroderma, eosinophilia and organ infiltration until HSCT can replace the compartment; it does not address the underlying replication defect.
Mechanism Target:
Omenn-Type Immune Dysregulation — Lymphodepletion and calcineurin inhibition dampen the activated oligoclonal T cells behind the dysregulation picture.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"and for which he received steroids, cyclosporine, and alemtuzumab"
The three agents given for the Omenn phenotype in the one patient who had it.
🔬

Diagnosis

3
Lymphocyte subset enumeration
Subset enumeration defines the immune diagnosis. In the Omenn patient the total CD3+ proportion was within range, so a bare T-cell count would have missed the defect; subset work showed near-absent naive CD4 and CD8 cells, a low CD8+ proportion and raised NK cells, and the naive-cell loss is what distinguishes a developmental failure from a peripheral one.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Immunological analysis prior to HSCT showed severely reduced naiïve CD4+ and CD8+ cells, low memory B cells, and high NK cells"
The subset findings that establish the T-cell deficiency.
T-cell receptor repertoire analysis
High-throughput TRB sequencing and V-alpha staining demonstrate the restricted, oligoclonal repertoire and the defect in early TCR recombination, which separate a developmental T-cell defect from a survival one.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination."
The repertoire and recombination findings that localise the lesion.
Exome sequencing with functional confirmation
Both patients were diagnosed by whole exome sequencing of a consanguineous trio, with the POLD3 variant prioritised on deleteriousness and phenotype overlap and then confirmed functionally — abolished subunit expression for one allele, and rescue of the cell-cycle defect by wild-type POLD3 for the other.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The cell cycle defect was rescued by transduction with WT POLD3."
The functional confirmation that the prioritised variant is causal.
📈

Progression

2
Infantile-onset recurrent infection
Both patients presented in infancy. The Omenn patient presented at three months with recurrent upper and lower respiratory infection progressing to acute respiratory distress, with the full Omenn picture; the Lebanese patient had recurrent infection from seven months and three siblings who had died by age five.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The index case presented at 4y with a history of recurrent infections from 7 months. His siblings had died at ages 3, 5, and 5 years."
The infantile onset and early-childhood sibling mortality in the Lebanese family.
Haematopoietic stem cell transplantation and post-transplant course
The Omenn patient underwent HSCT at six months from a matched unrelated donor and required a stem-cell boost for low chimerism; he manifested progressive neurological regression and died at four years. Transplantation corrects the immune compartment but does not address the non-haematopoietic features, and the neurological course was not arrested by it.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years."
The transplant and the fatal neurological course in the Omenn patient.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Two genetically confirmed patients in two unrelated consanguineous families: one Lebanese child homozygous for p.Ile10Thr, and one boy of Moroccan descent homozygous for p.Lys373Thr who presented as Omenn syndrome. Three siblings of the Lebanese patient died in early childhood of a comparable illness but were not genotyped, so they are not counted. No population estimate exists and rate_per_100000 is left unset rather than computed from two cases.
Show evidence (1 reference)
PMID:38099988 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome."
The point at which the entity was defined, which is what makes the current total of two the whole of the literature.
{ }

Source YAML

click to show 
name: Immunodeficiency 122
category: Mendelian
creation_date: "2026-10-01T20:28:15Z"
synonyms:
- IMD122
- POLD3 deficiency
- POLD3-associated combined immunodeficiency
- DNA polymerase delta 3 deficiency
- syndromic severe combined immunodeficiency due to POLD3 deficiency
disease_term:
  preferred_term: immunodeficiency 122
  term:
    id: MONDO:0971151
    label: immunodeficiency 122
description: >-
  IMD122 is the syndromic combined immunodeficiency caused by biallelic variants in POLD3, an
  accessory subunit of DNA polymerase delta. Two unrelated patients are published, each
  homozygous for a different missense variant: a Lebanese child of a consanguineous family with
  a syndromic SCID, neurodevelopmental delay and hearing loss, and a boy of Moroccan descent who
  presented as Omenn syndrome and died at four. Three further siblings of the first patient died
  in early childhood of a comparable illness but were not genotyped, so the genetically confirmed
  count is two.

  The mechanism is the same proliferation defect that underlies the sibling polymerase-delta
  immunodeficiencies POLD1 (IMD120) and POLD2. Polymerase delta is a heterotetramer: POLD1
  carries the catalytic activities, POLD2 is the scaffold, and POLD3 and POLD4 regulate the
  activity and stability of the complex and establish its contacts, with POLD3 in particular
  mediating the interaction with PCNA that the holoenzyme needs for processivity. A hypomorphic
  accessory subunit lowers the enzyme's output, which restricts how many cells can enter and
  complete S phase. Lymphocytes expand fastest on demand, so they fail first, and the disease
  presents as a T-cell deficiency.

  The two alleles reach that output by different routes, which is the useful part of having two
  patients. p.Ile10Thr sits in the POLD2-binding region and abolishes expression of POLD3 along
  with POLD1 and POLD2 — the destabilisation route, the same one the POLD1 CysB allele takes.
  p.Lys373Thr sits in a positively charged interdomain region thought to aid DNA binding, and
  leaves the expression of all three subunits intact while impairing function — the
  reduced-activity route. Different lesions, convergent phenotype, which is the argument that the
  disease follows from reduced polymerase delta output rather than from a property of one allele.

  Unlike the POLD1 patients, where DNA repair after genotoxic stress was reported normal, the
  Omenn patient's fibroblasts showed both a marked defect in S-phase entry and an increased
  number of double-strand-break-associated foci, so replicative stress and DNA damage are
  directly documented here. The cell-cycle defect was rescued by re-expressing wild-type POLD3,
  which establishes the direction of causation.

  Clinically it presents in infancy with recurrent infection, profound depletion of naive T
  cells, a restricted T-cell receptor repertoire and defective early TCR recombination. The
  Omenn patient had the full dysregulation picture — erythroderma, alopecia, eosinophilia,
  elevated IgE, lymphadenopathy, hepatosplenomegaly and an absent thymus — and received a
  haematopoietic stem cell transplant at six months. The Lebanese patient had low naive T cells
  with preserved B-cell numbers, sensorineural hearing loss and developmental delay. Both carry
  syndromic non-immune features, which is why the entry is classified as a combined
  immunodeficiency with syndromic features.
parents:
- Combined Immunodeficiency
- Inborn Errors of Immunity
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A monogenic inborn error of immunity presenting as a syndromic combined immunodeficiency,
      managed by immunology.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS Table 2, combined immunodeficiencies with associated or syndromic features. Both
      published patients carry non-immune syndromic features — sensorineural hearing loss and
      neurodevelopmental delay in the Lebanese patient, growth retardation and facial dysmorphism
      in the Omenn patient — alongside the T-cell defect, which is what distinguishes this from
      the plain combined-immunodeficiency classification used for the POLD1 sibling entry.
references:
- reference: PMID:37030525
  title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
- reference: PMID:38099988
  title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
- reference: PMID:27524497
  title: "POLD3 Is Haploinsufficient for DNA Replication in Mice."
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic in both families. Both patients are homozygous, each the child of a consanguineous
    union, with the variant segregating with autosomal recessive inheritance and confirmed by
    Sanger sequencing. Heterozygous carriers are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The identified variant in the POLD3 gene (NM_006591) was a homozygous variant in exon 10 (c.1118A > C) with a CADD score of 25 that segregated with autosomal recessive inheritance, as confirmed by Sanger sequencing"
    explanation: >-
      Homozygosity and segregation consistent with recessive inheritance in the Omenn patient,
      confirmed by a second method.
  - reference: PMID:37030525
    reference_title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
    explanation: >-
      The second homozygous genotype in a consanguineous family, which establishes recessive
      inheritance in a second independent kindred.
pathophysiology:
- name: Biallelic Hypomorphic POLD3 Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Two homozygous missense genotypes are published, one per family. The Lebanese patient is
    homozygous for c.29T>C, p.Ile10Thr, in the POLD2-binding region of POLD3; the Omenn patient
    is homozygous for c.1118A>C, p.Lys373Thr, in a positively charged interdomain region thought
    to aid polymerase activity and DNA binding.

    No null allele appears, and none is expected to: in mice POLD3 is essential for development
    and for viability in adult animals, and even heterozygous loss is haploinsufficient for
    stabilising the complex. A viable patient's alleles are hypomorphic by construction.
  genes:
  - preferred_term: POLD3
    term:
      id: hgnc:20932
      label: POLD3
  genetic_context:
    genes:
    - preferred_term: POLD3
      term:
        id: hgnc:20932
        label: POLD3
    allele_type: homozygous missense in each family — p.Ile10Thr in one, p.Lys373Thr in the other
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    notes: >-
      PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION, and the reasoning is not a hedge:
      complete POLD3 loss is embryonic lethal in mice and POLD3 is haploinsufficient even in the
      heterozygous state, so a viable patient's alleles must retain some function. One allele
      nonetheless abolishes detectable protein — the hypomorphism is at the level of the
      holoenzyme's residual output, not necessarily of each subunit's expression.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome."
    explanation: The Omenn patient's genotype, found and reported by this study.
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "WES identified a homozygous variant (c.29 T > C; p.I10T) in the POLD2 binding region of POLD3, and patient cells showed no expression of POLD3, POLD1, or POLD2."
    explanation: >-
      The Lebanese patient's genotype and the subunit location, quoted from this paper's summary
      of the concurrently published Mehawej case so both alleles are described from one source.
  downstream:
  - target: Destabilisation of the Polymerase Delta Complex
    causal_link_type: DIRECT
    description: >-
      The p.Ile10Thr route. The substitution lies in the POLD2-binding region and abolishes the
      steady-state amount of POLD3, POLD1 and POLD2 together — the complex cannot assemble, so all
      three measured subunits drop.
    evidence:
    - reference: PMID:37030525
      reference_title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "The homozygous POLD3Ile10Thr variant abolishes POLD3 as well as POLD1 and POLD2 expression."
      explanation: The loss of all three subunits in the destabilising-allele patient.
  - target: Impaired Polymerase Delta Function with Intact Complex
    causal_link_type: DIRECT
    description: >-
      The p.Lys373Thr route. Expression of all three subunits is preserved, so the complex
      assembles, but function is impaired — the distinct second mechanism reaching the same output.
    evidence:
    - reference: PMID:38099988
      reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Expression of not only POLD3 but also POLD1 and POLD2 were comparable to healthy control fibroblasts"
      explanation: >-
        Normal subunit expression in the Omenn patient, which is what separates this allele's
        mechanism from the destabilising one.
- name: Destabilisation of the Polymerase Delta Complex
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    POLD3 stabilises the POLD1-POLD2 interaction, so a variant in its POLD2-binding region does
    not inactivate one subunit, it lowers the amount of assembled enzyme. In the mouse, deleting
    Pold3 destabilises every member of the complex, which is the model for why one subunit's loss
    drags the others down.
  genes:
  - preferred_term: POLD3
    term:
      id: hgnc:20932
      label: POLD3
  cellular_components:
  - preferred_term: DNA polymerase delta complex
    term:
      id: GO:0043625
      label: delta DNA polymerase complex
    modifier: DECREASED
  evidence:
  - reference: PMID:27524497
    reference_title: "POLD3 Is Haploinsufficient for DNA Replication in Mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "we show that Pold3 deletion destabilizes all members of the Polδ complex, explaining its major role in DNA replication and the severe impact of its deficiency"
    explanation: >-
      The mechanism by which loss of one subunit lowers the whole complex, shown in the mouse.
      Graded INDIRECT and MODEL_ORGANISM because it is the murine result applied to the human
      destabilising allele, whose own subunit loss is the node's human evidence.
  downstream:
  - target: Impaired DNA Replication and S-Phase Entry
    causal_link_type: DIRECT
- name: Impaired Polymerase Delta Function with Intact Complex
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The second route to the same deficit. p.Lys373Thr leaves the complex assembled and all three
    subunits expressed at normal levels, but lies in a positively charged region implicated in
    DNA binding and polymerase processivity, so it compromises function rather than amount. The
    two families therefore differ in biochemistry and agree in phenotype, which is the argument
    that the disease follows from reduced polymerase delta output rather than from a property of
    one allele.
  genes:
  - preferred_term: POLD3
    term:
      id: hgnc:20932
      label: POLD3
  molecular_functions:
  - preferred_term: DNA-directed DNA polymerase activity
    term:
      id: GO:0003887
      label: DNA-directed DNA polymerase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The cell cycle defect was rescued by transduction with WT POLD3."
    explanation: >-
      Re-expressing wild-type POLD3 corrected the cellular phenotype, which establishes that the
      variant impairs POLD3 function and that the function is causal for the defect downstream.
  downstream:
  - target: Impaired DNA Replication and S-Phase Entry
    causal_link_type: DIRECT
- name: Impaired DNA Replication and S-Phase Entry
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    POLD3 mediates the complex's interaction with PCNA, which the holoenzyme needs for activity
    and processivity, so less functional polymerase delta means fewer cells begin and complete
    DNA synthesis. The Omenn patient's fibroblasts showed a marked defect in S-phase entry and
    reduced proliferation over a week in culture, and the defect was at the entry to S phase
    rather than in elongation.
  biological_processes:
  - preferred_term: DNA replication initiation
    term:
      id: GO:0006270
      label: DNA replication initiation
    modifier: DECREASED
  - preferred_term: cell cycle
    term:
      id: GO:0007049
      label: cell cycle
    modifier: DECREASED
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "it appears that the reduced proliferation in patient fibroblasts is caused by cellular arrest at the entry to the S phase"
    explanation: The localisation of the defect to S-phase entry in the patient's cells.
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "POLD3 mediates interaction with proliferating cell nuclear antigen (PCNA), which is essential for PolD activity and processivity"
    explanation: >-
      The specific role of POLD3 — the PCNA interaction — that a POLD3 lesion disrupts. Quoted
      from this paper's introduction, hence quote_role BACKGROUND; it is the node's mechanistic
      premise rather than a measurement.
  downstream:
  - target: Replication-Associated DNA Damage
    causal_link_type: DIRECT
  - target: Impaired T Cell Development and Proliferation
    causal_link_type: DIRECT
- name: Replication-Associated DNA Damage
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Unresolved replicative stress produces double-strand breaks. The Omenn patient's fibroblasts
    carried an increased number of double-strand-break-associated foci despite normal subunit
    expression, which is the direct evidence of DNA damage that the POLD1 patients lacked. This
    is the branch that pushes the phenotype towards the DNA-damage end of the polymerase-delta
    spectrum, consistent with the Omenn rather than the milder CID presentation.
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components."
    explanation: The replication-associated DNA damage measured in the patient's cells.
  downstream:
  - target: Impaired T Cell Development and Proliferation
    causal_link_type: DIRECT
- name: Impaired T Cell Development and Proliferation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Antigen-receptor recombination and clonal expansion both require heightened, accurate DNA
    replication, so a replication-limited progenitor pool fails at T-cell development first. The
    Omenn patient had a defect in the early stages of TCR recombination, severely reduced naive T
    cells and a restricted repertoire; the Lebanese patient had low naive T cells with preserved
    B-cell numbers. The B-cell compartment is comparatively spared, which is why the defect
    presents as T-cell rather than purely combined at the cellular level.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell receptor V(D)J recombination
    term:
      id: GO:0033153
      label: T cell receptor V(D)J recombination
    modifier: DECREASED
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination."
    explanation: >-
      The three joined features — naive T-cell loss, restricted repertoire and defective early
      recombination — that make this a developmental T-cell defect.
  downstream:
  - target: Decreased CD8+ T Cell Proportion
    causal_link_type: DIRECT
  - target: Decreased Naive T Cell Proportion
    causal_link_type: DIRECT
  - target: Restricted T Cell Receptor Repertoire
    causal_link_type: DIRECT
  - target: Oligoclonal T Cell Expansion
    causal_link_type: DIRECT
  - target: Severe Combined Immunodeficiency
    causal_link_type: DIRECT
  - target: Recurrent Infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thymic Aplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn tentatively: the Omenn patient had no demonstrable thymus on imaging, which in a
      proliferation-limited T-cell defect is consistent with failed thymic cellularity, but no
      thymic histology was obtained and the edge is an inference from the imaging rather than a
      measured step.
- name: Oligoclonal T Cell Expansion
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    A repertoire that is both small and oligoclonal. In the Omenn patient the TCR V-beta
    repertoire was oligoclonal and TRB diversity was reduced to about a third of a healthy
    control, while B-cell IgH diversity was comparatively preserved — the same asymmetry seen in
    the POLD1 sibling disease. An oligoclonal, autoreactive T-cell expansion on a background of
    profound T-cell deficiency is the immunological basis of the Omenn presentation.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
    explanation: The oligoclonal repertoire measured in the Omenn patient, alongside the IgE and eosinophilia that accompany it.
  downstream:
  - target: Omenn-Type Immune Dysregulation
    causal_link_type: DIRECT
    description: >-
      Oligoclonal, poorly selected T cells drive the erythroderma, eosinophilia and raised IgE
      that define the Omenn phenotype. The step is the standard reading of Omenn immunobiology
      applied to this patient's measured repertoire rather than a finding specific to POLD3.
- name: Omenn-Type Immune Dysregulation
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    The dysregulation syndrome seen in the Omenn patient: erythroderma, alopecia, generalised
    lymphadenopathy, hepatosplenomegaly, eosinophilia and elevated IgE. Graded PROVISIONAL
    because it rests on one patient; the Lebanese patient did not have the Omenn picture, so
    whether Omenn-type dysregulation is a feature of POLD3 deficiency or of this particular allele
    and course is not settled.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
    explanation: The clinical dysregulation features in the Omenn patient.
  downstream:
  - target: Erythroderma
    causal_link_type: DIRECT
  - target: Alopecia
    causal_link_type: DIRECT
  - target: Eosinophilia
    causal_link_type: DIRECT
  - target: Elevated Serum IgE
    causal_link_type: DIRECT
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
  - target: Lymphadenopathy
    causal_link_type: DIRECT
  - target: Increased Natural Killer Cell Count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn tentatively. The raised NK proportion was measured alongside the Omenn picture before
      transplant, but the source offers no mechanism for it, and a relative NK excess can follow
      from a contracted T-cell compartment rather than from NK expansion as such.
- name: Syndromic Developmental and Sensorineural Features
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Neurodevelopmental delay in both patients, sensorineural hearing loss in the Lebanese
    patient, and growth retardation with facial dysmorphism in the Omenn patient. The mechanism
    is assumed rather than shown: polymerase delta is required wherever cells divide, so a general
    replication restriction should affect development — and the mouse models the point, with
    replication-stress features reminiscent of microcephaly syndromes. No non-haematopoietic
    tissue was examined in either patient, and the Omenn patient's post-transplant neurological
    regression confounds the developmental attribution, so the node is graded HYPOTHETICAL.
  evidence:
  - reference: PMID:37030525
    reference_title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
    explanation: >-
      That the developmental and sensorineural features are part of the described syndrome. It
      supports their inclusion in the entity, not the replication mechanism this node proposes
      for them, which is why the node is HYPOTHETICAL.
  downstream:
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Growth Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Facial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Severe Combined Immunodeficiency
  category: Immune
  description: >-
    Both patients meet a combined-immunodeficiency picture; the Omenn patient fulfilled Omenn
    SCID criteria and the Lebanese patient was reported as a syndromic SCID. This is the
    unifying immune diagnosis of the entity.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  notes: 2 of 2 genotyped patients.
  evidence:
  - reference: PMID:37030525
    reference_title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our findings implicate POLD3 deficiency as a novel cause of syndromic SCID."
    explanation: The entity's defining immune phenotype, stated as the paper's conclusion.
- name: Recurrent Infections
  category: Immune
  description: >-
    Recurrent infection from infancy in both patients — from seven months of age in the Lebanese
    patient, and recurrent upper and lower respiratory tract infection with bacterial
    superinfection in the Omenn patient. It is the presenting feature of the disease.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
    temporality: RECURRENT
  notes: 2 of 2 genotyped patients.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The index case presented at 4y with a history of recurrent infections from 7 months. His siblings had died at ages 3, 5, and 5 years."
    explanation: >-
      The recurrent-infection history in the Lebanese patient, with the three early-childhood
      sibling deaths that frame the family's burden. Quoted from this paper's summary of the
      Mehawej case.
- name: Decreased CD8+ T Cell Proportion
  category: Immune
  description: >-
    A low CD8+ T-cell proportion in the Omenn patient before transplant, 3% against a reference
    range of 12-28%, while the total CD3+ and CD4+ proportions were within range. The total T-cell
    compartment was therefore not reduced; what was lost was the naive pool and the CD8+ subset.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Decreased CD8+ T cell proportion
    term:
      id: HP:0005415
      label: Decreased total CD8+ T cell proportion
  notes: >-
    1 of 2 genotyped patients (the Omenn patient). Bound to the proportion term rather than
    HP:5210425 (Decreased total CD8+ T cell number) because the source reports a percentage, not
    an absolute count. HPO defines the proportion as a percentage of CD3+ T cells; the source table
    does not state its denominator, and its CD3+ value of 58% suggests a percentage of lymphocytes.
    Either way the CD8+ fraction is low while CD3+ and CD4+ are in range. Subset counts for the
    Lebanese patient are not reported beyond low naive T cells, so this is not recorded for him.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "CD8 + (%) | 3 | 12–28"
    explanation: >-
      Table 1 row for the Omenn patient before transplant: 3% CD8+ cells against a 12-28%
      reference range.
- name: Decreased Naive T Cell Proportion
  category: Immune
  description: >-
    Naive T cells are severely reduced in both patients, the cellular signature of a compartment
    that cannot replace what it spends. In the Lebanese patient low naive T cells coexist with
    normal B-cell numbers, which localises the lesion to the T lineage.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased naive T cell proportion
    term:
      id: HP:0031397
      label: Decreased naive T cell proportion
  notes: 2 of 2 genotyped patients.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had low naïve T cells but normal B cell counts, and he had normal IgG and IgM but partially deficient IgA."
    explanation: >-
      The naive-T-cell loss with preserved B-cell numbers in the Lebanese patient, quoted from
      this paper's summary of that case.
- name: Restricted T Cell Receptor Repertoire
  category: Immune
  description: >-
    An oligoclonal, contracted T-cell receptor repertoire in the Omenn patient, with TRB
    diversity reduced to roughly a third of a healthy control while IgH diversity was largely
    preserved.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Oligoclonal, restricted T-cell receptor repertoire
    term:
      id: HP:0025845
      label: Abnormal TCR repertoire
  notes: >-
    1 of 2 genotyped patients (measured in the Omenn patient). Bound to the general
    abnormal-TCR-repertoire term because HPO has no term for a restricted or oligoclonal
    repertoire specifically; the restriction is carried in preferred_term and description.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Prior to HSCT, the patient displayed severely reduced levels of naïve T cells and a restricted TCR Vβ repertoire"
    explanation: The restricted TCR V-beta repertoire measured in the Omenn patient before transplant.
- name: Thymic Aplasia
  category: Immune
  description: >-
    No thymus demonstrable on chest X-ray or ultrasound in the Omenn patient. A failure to
    visualise the thymus in a profound T-cell deficiency is consistent with absent thymic
    cellularity, though it is an imaging finding rather than a histological one.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Thymus not visualised on imaging
    term:
      id: HP:0005359
      label: Aplasia of the thymus
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Chest X-ray and ultrasound failed to show a thymus."
    explanation: The absent thymus on imaging in the Omenn patient.
- name: Erythroderma
  category: Integumentary
  description: Erythroderma in the Omenn patient, part of the Omenn dysregulation picture.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
    explanation: The erythroderma in the Omenn patient.
- name: Alopecia
  category: Integumentary
  description: Alopecia in the Omenn patient, part of the Omenn dysregulation picture.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
    explanation: The alopecia in the Omenn patient.
- name: Eosinophilia
  category: Immune
  description: Eosinophilia in the Omenn patient, a component of the Omenn phenotype.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
    explanation: The eosinophilia in the Omenn patient.
- name: Elevated Serum IgE
  category: Immune
  description: Elevated serum IgE in the Omenn patient, a component of the Omenn phenotype.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Elevated serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient had elevated serum IgE, eosinophilia, and an oligoclonal T-cell receptor variable β-chain (TCR Vβ) repertoire as measured by flow cytometry"
    explanation: The elevated IgE in the Omenn patient.
- name: Hepatosplenomegaly
  category: Abdominal
  description: Hepatosplenomegaly in the Omenn patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
    explanation: The hepatosplenomegaly in the Omenn patient.
- name: Lymphadenopathy
  category: Immune
  description: Generalised lymphadenopathy in the Omenn patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Generalized lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  notes: 1 of 2 genotyped patients (the Omenn patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had alopecia, generalized lymphadenopathy, hepatosplenomegaly, and erythroderma, with preceding recurrent bacterial superinfection"
    explanation: The lymphadenopathy in the Omenn patient.
- name: Increased Natural Killer Cell Count
  category: Immune
  description: >-
    High NK cells in the Omenn patient before transplant, 32% of lymphocytes against a reference
    range of 4-18%.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Increased natural killer cell proportion
    term:
      id: HP:6000677
      label: Increased total natural killer cell count
  notes: >-
    1 of 2 genotyped patients (the Omenn patient). The source reports a percentage of lymphocytes,
    not an absolute count; HPO has no NK-proportion term, so the count term is bound and the
    measure is carried in preferred_term and description.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "NK (%) | 32 | 4–18"
    explanation: Table 1 row for the Omenn patient before transplant, above the reference range.
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Immunological analysis prior to HSCT showed severely reduced naiïve CD4+ and CD8+ cells, low memory B cells, and high NK cells"
    explanation: The authors' own reading of the subset analysis, naming the NK excess.
- name: Decreased Circulating IgA
  category: Immune
  description: >-
    Partially deficient IgA with normal IgG and IgM in the Lebanese patient — a milder humoral
    picture than the Omenn patient's, and one that fits the comparatively preserved B-cell
    compartment seen across the polymerase-delta immunodeficiencies.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Partial IgA deficiency
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  notes: 1 of 2 genotyped patients (the Lebanese patient).
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He had low naïve T cells but normal B cell counts, and he had normal IgG and IgM but partially deficient IgA."
    explanation: >-
      The Lebanese patient's humoral picture, quoted from this paper's summary of that case.
- name: Sensorineural Hearing Loss
  category: Otologic
  description: Sensorineural hearing loss in the Lebanese patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    1 of 2 genotyped patients (the Lebanese patient). The Omenn patient's hearing is not
    reported, so this is recorded as present in one rather than variable across both.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, the patient had sensorineural hearing loss and developmental delay."
    explanation: >-
      The hearing loss and developmental delay in the Lebanese patient, quoted from this paper's
      summary of that case.
- name: Global Developmental Delay
  category: Nervous System
  description: >-
    Neurodevelopmental delay in both patients. In the Omenn patient it progressed to neurological
    regression after transplant, which complicates attributing it to the polymerase defect alone.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: 2 of 2 genotyped patients.
  evidence:
  - reference: PMID:37030525
    reference_title: "POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss."
    explanation: The neurodevelopmental delay named in the Lebanese patient's presentation.
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
    explanation: The developmental delay in the Omenn patient at three years, the second of the two patients.
- name: Growth Delay
  category: Growth
  description: Growth retardation in the Omenn patient at three years, part of the syndromic picture.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  notes: >-
    1 of 2 genotyped patients (the Omenn patient). His post-transplant course confounds the
    attribution, since conditioning and chronic illness also retard growth.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
    explanation: The growth retardation in the Omenn patient at three years.
- name: Facial Dysmorphism
  category: Craniofacial
  description: >-
    Facial dysmorphism in the Omenn patient at three years. The source names it without
    describing the individual features.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  notes: >-
    1 of 2 genotyped patients (the Omenn patient). Facial features are not reported for the
    Lebanese patient.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At 3 years, he had severe growth retardation, developmental delay, and facial dysmorphy."
    explanation: The facial dysmorphism in the Omenn patient at three years.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Two genetically confirmed patients in two unrelated consanguineous families: one Lebanese
    child homozygous for p.Ile10Thr, and one boy of Moroccan descent homozygous for p.Lys373Thr
    who presented as Omenn syndrome. Three siblings of the Lebanese patient died in early
    childhood of a comparable illness but were not genotyped, so they are not counted. No
    population estimate exists and rate_per_100000 is left unset rather than computed from two
    cases.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome."
    explanation: >-
      The point at which the entity was defined, which is what makes the current total of two the
      whole of the literature.
progression:
- phase: Infantile-onset recurrent infection
  notes: >-
    Both patients presented in infancy. The Omenn patient presented at three months with
    recurrent upper and lower respiratory infection progressing to acute respiratory distress,
    with the full Omenn picture; the Lebanese patient had recurrent infection from seven months
    and three siblings who had died by age five.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The index case presented at 4y with a history of recurrent infections from 7 months. His siblings had died at ages 3, 5, and 5 years."
    explanation: The infantile onset and early-childhood sibling mortality in the Lebanese family.
- phase: Haematopoietic stem cell transplantation and post-transplant course
  notes: >-
    The Omenn patient underwent HSCT at six months from a matched unrelated donor and required a
    stem-cell boost for low chimerism; he manifested progressive neurological regression and died
    at four years. Transplantation corrects the immune compartment but does not address the
    non-haematopoietic features, and the neurological course was not arrested by it.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years."
    explanation: The transplant and the fatal neurological course in the Omenn patient.
genetic:
- name: POLD3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: POLD3
    term:
      id: hgnc:20932
      label: POLD3
  notes: >-
    The causal gene. POLD3 is an accessory subunit of DNA polymerase delta: it stabilises the
    POLD1-POLD2 interaction and, through a C-terminal PIP box, mediates the complex's interaction
    with PCNA. Both published alleles are homozygous missense. p.Ile10Thr abolishes expression of
    all three subunits (the destabilising route); p.Lys373Thr leaves expression intact but
    impairs function (the reduced-activity route). Unlike POLD1, no cancer-predisposition or
    progeroid allele class is described for POLD3 in humans.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "POLD3, with POLD2 and POLD4, regulate the activity of POLD1, the activity and stability of PolD, and establish protein–protein interactions"
    explanation: >-
      POLD3's role in the complex, quoted from this paper's introduction (hence quote_role
      BACKGROUND) as the established biology a POLD3 lesion disrupts.
diagnosis:
- name: Lymphocyte subset enumeration
  description: >-
    Subset enumeration defines the immune diagnosis. In the Omenn patient the total CD3+
    proportion was within range, so a bare T-cell count would have missed the defect; subset work
    showed near-absent naive CD4 and CD8 cells, a low CD8+ proportion and raised NK cells, and the
    naive-cell loss is what distinguishes a developmental failure from a peripheral one.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Immunological analysis prior to HSCT showed severely reduced naiïve CD4+ and CD8+ cells, low memory B cells, and high NK cells"
    explanation: The subset findings that establish the T-cell deficiency.
- name: T-cell receptor repertoire analysis
  description: >-
    High-throughput TRB sequencing and V-alpha staining demonstrate the restricted, oligoclonal
    repertoire and the defect in early TCR recombination, which separate a developmental T-cell
    defect from a survival one.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination."
    explanation: The repertoire and recombination findings that localise the lesion.
- name: Exome sequencing with functional confirmation
  description: >-
    Both patients were diagnosed by whole exome sequencing of a consanguineous trio, with the
    POLD3 variant prioritised on deleteriousness and phenotype overlap and then confirmed
    functionally — abolished subunit expression for one allele, and rescue of the cell-cycle
    defect by wild-type POLD3 for the other.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The cell cycle defect was rescued by transduction with WT POLD3."
    explanation: The functional confirmation that the prioritised variant is causal.
treatments:
- name: Haematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    The only reported route to correcting the immune defect. The Omenn patient received HSCT at
    six months from a 10/10 matched unrelated donor after conditioning, with a stem-cell boost
    for low chimerism. It replaces the haematopoietic compartment with cells carrying two working
    POLD3 alleles, but does nothing for the non-haematopoietic features — this patient's
    neurological regression continued and he died at four. Whether a defect in the replicative
    polymerase raises conditioning-related toxicity, as it is feared to in the POLD1 sibling
    disease, is not addressed in either report.
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired T Cell Development and Proliferation
    description: >-
      Donor cells with functional POLD3 remove the proliferation ceiling in the lineage where it
      matters. It leaves the developmental and sensorineural features untouched.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He underwent hematopoietic stem cell transplantation (HSCT) at 6 months with a 10/10 matched unrelated donor, following conditioning with alemtuzumab, treosulfan, and fiudarabine, with the need for a stem cell boost ~ 8 months later because of chimerism < 20%."
    explanation: >-
      The transplant and its course in the Omenn patient. The source's "fiudarabine" is an OCR
      artefact for fludarabine, quoted verbatim as the snippet must match the cache.
  notes: >-
    One transplanted patient, who died of a progressive neurological course that transplantation
    did not arrest. This records the only reported disease-directed intervention, not a standard
    of care.
- name: Immunosuppression for Omenn Syndrome
  description: >-
    Before transplant the Omenn patient received steroids, cyclosporine and alemtuzumab for the
    Omenn picture. The aim is to suppress the oligoclonal, activated T cells driving the
    erythroderma, eosinophilia and organ infiltration until HSCT can replace the compartment; it
    does not address the underlying replication defect.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: cyclosporine
      term:
        id: CHEBI:4031
        label: cyclosporin A
    - preferred_term: alemtuzumab
      term:
        id: NCIT:C1681
        label: Alemtuzumab
  target_mechanisms:
  - target: Omenn-Type Immune Dysregulation
    description: >-
      Lymphodepletion and calcineurin inhibition dampen the activated oligoclonal T cells behind
      the dysregulation picture.
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "and for which he received steroids, cyclosporine, and alemtuzumab"
    explanation: The three agents given for the Omenn phenotype in the one patient who had it.
  notes: >-
    One patient. The source gives no doses, sequence or response, so this records what was given,
    not its effect. therapeutic_modality is left unset because the regimen combines small
    molecules and a monoclonal antibody and the slot takes one value.
discussions:
- discussion_id: imd122_omenn_vs_cid_spectrum
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Why does one POLD3 genotype present as florid Omenn syndrome with documented DNA damage while
    the other presents as a milder syndromic CID — is it the allele, the degree of residual
    function, or something else?
  rationale: >-
    The two patients differ along two axes at once, which is exactly what makes the question hard.
    The Omenn patient (p.Lys373Thr) has normal subunit expression but impaired function, a marked
    S-phase-entry defect and increased double-strand-break foci, and the full dysregulation
    picture. The Lebanese patient (p.Ile10Thr) has abolished subunit expression — a seemingly more
    severe molecular lesion — but a milder clinical picture of syndromic CID with preserved B-cell
    numbers and no reported Omenn features.

    So the more complete loss of protein does not map to the more severe clinical picture, which
    argues the phenotype is set by residual holoenzyme output and by which downstream processes it
    limits rather than by subunit abundance. Distinguishing the possibilities needs the missing
    measurements: cell-cycle and DNA-damage assays were done only in the Omenn patient, so there
    is no functional comparison of the two alleles in the same assay.
  attaches_to:
  - pathophysiology#Destabilisation of the Polymerase Delta Complex
  - pathophysiology#Impaired Polymerase Delta Function with Intact Complex
  - pathophysiology#Replication-Associated DNA Damage
  evidence:
  - reference: PMID:38099988
    reference_title: "Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components."
    explanation: >-
      The key asymmetry: the clinically more severe (Omenn) patient has normal subunit
      expression, so the severity cannot be read off protein abundance.
- discussion_id: imd122_syndromic_attribution
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Are the developmental and sensorineural features of POLD3 deficiency a direct consequence of
    reduced polymerase delta in dividing non-haematopoietic tissue, as the mouse replication-stress
    phenotype would suggest, or are they confounded by infection and transplant course in the two
    human patients?
  rationale: >-
    The mouse supplies a clean mechanistic prediction: Pold3 loss causes embryonic replication
    stress with brain-preferential phenotypes reminiscent of microcephaly syndromes, so a
    hypomorphic human should show developmental effects. The human data cannot confirm it. No
    non-haematopoietic tissue was examined in either patient; the Lebanese patient's hearing loss
    and developmental delay are reported without mechanism; and the Omenn patient's
    neurodevelopmental course is confounded by his transplant, conditioning and fatal neurological
    regression. The model predicts a direct developmental effect that the human evidence can
    neither establish nor exclude — classified HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP
    because the model evidence exists and the open question is its translational validity, not the
    absence of any evidence.
  attaches_to:
  - pathophysiology#Syndromic Developmental and Sensorineural Features
  - phenotypes#Sensorineural Hearing Loss
  - phenotypes#Global Developmental Delay
  evidence:
  - reference: PMID:27524497
    reference_title: "POLD3 Is Haploinsufficient for DNA Replication in Mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "POLD3 is essential for mouse development and is also required for viability in adult animals"
    explanation: >-
      The model evidence that a POLD3 deficit affects development, which is what makes this a
      model-to-human validity question rather than an absence of evidence.
notes: >-
  Scope and patient count. Two genetically confirmed POLD3 patients are published, each
  homozygous for a different missense variant in an unrelated consanguineous family: p.Ile10Thr
  (Mehawej, Lebanese) and p.Lys373Thr (Riestra, Omenn, Moroccan descent). Three siblings of the
  Lebanese patient died in early childhood of a comparable illness but were not genotyped and are
  not counted here.

  Source attribution. The Mehawej report (PMID:37030525) is abstract-only in the cache; the
  Riestra report (PMID:38099988) is full text and, in its "while this manuscript was in
  preparation" paragraph, summarises the Mehawej patient. Several Lebanese-patient phenotypes are
  therefore quoted from the Riestra paper's summary of that case rather than from the Mehawej
  abstract — the snippet names the patient ("The index case presented at 4y") so the attribution
  is checkable, and the explanation says which paper and which patient each quote belongs to.

  GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and
  StatPearls against the committed Bookshelf index.

  Relationship to the sibling entries. IMD120 (POLD1) and the POLD2 deficiency share this
  mechanism — reduced polymerase delta output causing a proliferation-limited T-cell defect — and
  the three are reported together in the literature as one emerging subgroup. This entry reuses
  that framing where the POLD3 evidence supports it, and notes where POLD3 differs: direct
  documentation of replicative DNA damage (double-strand-break foci), the Omenn presentation in
  one patient, and the absence of a described cancer-predisposition allele class, which POLD1
  has.

  What is not curated. The broader POLD3 literature is dominated by its roles in break-induced
  replication, translesion synthesis and telomere maintenance in cancer cells. That is not a
  mechanism of this inherited immunodeficiency and is left out rather than included with a caveat;
  the mouse haploinsufficiency paper (PMID:27524497) is cited only for the complex-destabilisation
  and developmental-requirement points that bear on the human disease.
📚

References & Deep Research

References

3
PMID:37030525
POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.
No top-level findings curated for this source.
PMID:38099988
Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.
No top-level findings curated for this source.
PMID:27524497
POLD3 Is Haploinsufficient for DNA Replication in Mice.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Immunodeficiency 122 (POLD3) · 2026-10-01T20:46:40Z · View source

De novo curation of IMD122 (POLD3, MONDO:0971151) from the two published POLD3-deficiency reports plus the mouse Pold3 haploinsufficiency paper. Primary sources: PMID:38099988 (Riestra 2023, full text, Omenn patient, p.Lys373Thr) and PMID:37030525 (Mehawej 2023, abstract-only, Lebanese syndromic SCID patient, p.Ile10Thr); PMID:27524497 for the complex-destabilisation and developmental-requirement mouse evidence. Deep research: one openscientist run (research/Immunodeficiency_122-deep-research-openscientist.md); its term-validation section flagged NCIT:C603 mislabelled as Immunoglobulin Therapy (NCIT calls it Isotretinoin) which was not used, and confirmed no POLD3 human immunodeficiency papers beyond the two curated. Two genotyped patients total; three ungenotyped deceased siblings of the Mehawej patient are noted but not counted. Framed consistently with the sibling IMD120 (POLD1) entry: same proliferation-defect mechanism, two convergent allele routes (p.Ile10Thr abolishes POLD1/2/3 expression; p.Lys373Thr preserves expression but impairs function with normal subunit levels and rescue by WT POLD3). Within-paper attribution care: Mehawej-patient phenotypes are quoted from PMID:38099988's own summary paragraph of that case, with the snippet naming the patient so the assignment is checkable. Classified IUIS Table 2 (combined immunodeficiency with syndromic features) because both patients carry non-immune syndromic features. Pathograph: 9 pathophysiology nodes wired to 15 phenotypes via causal edges; one OPEN_QUESTION discussion (Omenn-vs-CID severity not tracking subunit abundance) and one HUMAN_MODEL_MISMATCH discussion (mouse developmental phenotype vs unconfirmed human developmental attribution). Validation on final tree: just validate (schema+terms), count-verified-snippets 41/41, validate-terms, validate-disorders (41 snippets, 44 titles, 0 issues), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-snippet-length, check-title-snippets, check-snippet-grading, check-enum-values, check-coarse-phenotypes, check-reference-titles, check-gene-activity-grounding, check-genereviews (NO_CHAPTER for GeneReviews and StatPearls). Deleted stub stubs/Immunodeficiency_122.yaml.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 2026-10-01T20:43:23.878056

1. Disease Information

  • Overview: IMD122 is a monogenic inborn error of immunity in the category of combined immunodeficiencies with syndromic/associated features (per IUIS classification). It combines a profound T-cell (± B/NK) defect with neurodevelopmental, auditory, and ectodermal manifestations due to a defect in genome replication/maintenance.
  • Key identifiers:
  • OMIM phenotype: 620869 (Immunodeficiency 122)
  • MONDO: MONDO:0971151
  • DOID: 0061088; MedGen/UMLS: C5935632
  • Orphanet: no dedicated code identified (newly described; would fall under "Combined immunodeficiency")
  • ICD-11: maps to 4A00 (Primary immunodeficiencies) / ICD-10 D81.x (combined immunodeficiencies)
  • MeSH: no specific descriptor; closest = Severe Combined Immunodeficiency (D016511); phenotype also = Omenn syndrome
  • Synonyms / alternative names: IMD122; POLD3 deficiency; DNA polymerase delta 3 deficiency; syndromic SCID due to POLD3; autosomal-recessive polymerase δ (PolD) deficiency (POLD3 type); POLD3-related Omenn syndrome.
  • Evidence source: Individual-patient (case report) level — two probands total (PMID 37030525; PMID 38099988).

2. Etiology

  • Causal factor (genetic): Biallelic (homozygous) pathogenic missense variants in POLD3 (AR). Both reported patients were offspring of consanguineous unions.
  • "Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID)" (PMID 37030525).
  • Genetic risk factors: The causal variants themselves (p.Ile10Thr; p.K373T). No susceptibility loci or modifier genes identified (too few cases). Consanguinity is the principal risk context. POLD3 is strongly LoF-intolerant (gnomAD pLI 0.994, LOEUF 0.48), so only hypomorphic missense alleles—retaining partial function—cause viable disease; complete LoF is presumed lethal (mouse null embryonic-lethal, PMID 29447390).
  • Environmental risk factors: None established; disease is fully genetically determined. Infectious exposures are consequences (opportunistic infection due to immunodeficiency), not causes.
  • Protective factors: None reported (genetic or environmental). Not applicable at the population level given rarity.
  • Gene–environment interactions: Not characterized. Mechanistically, exogenous genotoxic/replication stressors (UV, chemotherapeutics, oxidative stress) would be predicted to aggravate the underlying replication defect (inferred, not demonstrated).

3. Phenotypes

Onset neonatal/congenital, severity severe, course progressive. Frequencies are qualitative (n=2). HPO terms derived from OMIM:620869 annotation.

Immune / laboratory abnormalities: - Severe combined immunodeficiency — HP:0000958 - Decreased total T cells — HP:0500093; decreased naive CD4+ (HP:0001744) and naive CD8+ (HP:0005359) proportions; oligoclonal T-cell expansion — HP:0010975 - Reduced NK cell count — HP:0000407; abnormal B-cell count — HP:0410243; decreased unswitched memory B cells — HP:0040218 - Decreased IgG — HP:0001019; abnormal IgM — HP:0004315; increased IgE — HP:0002716; eosinophilia — HP:0001999 - Thymic aplasia/hypoplasia — HP:0004430

Omenn-syndrome features (clinical signs/physical): - Erythroderma — HP:0410377; alopecia — HP:0008404; lymphadenopathy — HP:0002110; hepatomegaly — HP:0004429; splenomegaly — HP:0002783

Infections (symptoms): recurrent viral — HP:0002788; bacterial — HP:0001270; upper (HP:0001263) and lower (HP:0032126) respiratory infections; bronchiectasis — HP:0002007

Neurodevelopmental (behavioral/developmental): global developmental delay — HP:0001596; motor delay — HP:0002718; (progressive neurological regression in the Omenn patient)

Sensory: sensorineural hearing impairment — HP:0001880

Craniofacial / ectodermal (physical): frontal bossing — HP:0003212; abnormal facial shape — HP:0410378; enamel hypoplasia — HP:0011968; nail dystrophy — HP:0031430; dry skin — HP:0005403

Feeding/allergy: feeding difficulties — HP:0002240; food allergy — HP:0006297

Quality-of-life impact: profound—life-threatening infections, failure to thrive, developmental disability, deafness; without HSCT, SCID is uniformly fatal in infancy. Formal QoL instruments (EQ-5D/SF-36) not applicable/available.

4. Genetic / Molecular Information

  • Causal gene: POLD3 — HGNC:20932; NCBI Gene 10714; Ensembl ENSG00000077514; cytoband 11q13.4 (GRCh38 chr11:74,493,851–74,669,117, + strand); transcript NM_006591.3; protein UniProt Q15054 (466 aa, "DNA polymerase delta subunit 3", p66/p68).
  • Pathogenic variants (both germline, homozygous, missense): | Variant (cDNA/protein) | Patient | Classification | Consequence | |---|---|---|---| | NM_006591.3:c.29T>C, p.Ile10Thr | Lebanese, syndromic SCID (PMID 37030525) | Pathogenic (AR) | Abolishes POLD3 and POLD1/POLD2 protein expression → complex destabilization | | c.1118A>C, p.Lys373Thr (p.K373T) | Omenn syndrome (PMID 38099988) | Pathogenic (AR) | Normal PolD subunit levels but defective function → S-phase defect, ↑dsDNA breaks (rescued by WT POLD3) |
  • Variant type/class: missense (both). No nonsense/frameshift/splice/structural variants reported (consistent with LoF intolerance).
  • Allele frequency: both variants are private/ultra-rare, essentially absent from gnomAD; gene-level LoF constraint pLI 0.994, LOEUF 0.48, LoF o/e 0.33 (missense unconstrained, mis_z 0.76).
  • Somatic vs germline: germline.
  • Functional consequence: loss/reduction of function (hypomorphic). p.Ile10Thr → destabilization of the entire Pol δ heterocomplex; p.K373T → intrinsic functional impairment with preserved assembly.
  • Modifier genes: none identified.
  • Epigenetic information: none reported for this disorder.
  • Chromosomal abnormalities: none (point mutations only). Downstream, POLD3 deficiency causes acquired genomic instability (chromosome breaks, micronuclei, aneuploidy — shown in mouse/cell models, PMID 29447390).

5. Environmental Information

  • Environmental factors: none causative. IMD122 is a monogenic disorder.
  • Lifestyle factors: not applicable (congenital, infantile-lethal).
  • Infectious agents: not causal but central to morbidity—patients suffer opportunistic and recurrent viral, bacterial, and respiratory infections secondary to the immunodeficiency (HP:0002788/HP:0001270/HP:0032126). Typical SCID pathogens (inferred from SCID literature): Pneumocystis jirovecii, CMV, adenovirus, RSV, candida; live-vaccine organisms (BCG, rotavirus) are contraindicated.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic hypomorphic missense variant in POLD3 (p.Ile10Thr or p.K373T) → reduced functional DNA polymerase δ, either by destabilizing/degrading the POLD1–POLD2–POLD3(–POLD4) complex (p.Ile10Thr abolishes POLD1/POLD2/POLD3 expression) or by impairing complex function with preserved subunit levels (p.K373T). (Demonstrated in vitro.)
  2. Reduced Pol δ activity → impaired high-fidelity DNA replication (leading- and lagging-strand synthesis, loss of PCNA-stimulated processivity) and reduced DNA repair capacity. (Demonstrated — UniProt-annotated functions; Conde POLD1/POLD2 data PMID 31449058.)
  3. → Replicative stress: defective S-phase entry/progression and accumulation of DNA double-strand breaks (γH2AX foci); the defect is rescued by wild-type POLD3, establishing causality. (Demonstrated — PMID 38099988; analogous mouse data PMID 29447390: extended S-phase, telomere loss, chromosome breaks, micronuclei, aneuploidy, DDR via ATR/ATM/53BP1/RIF1.) 4a. Immune branch: replication stress plus a defect in the early stages of TCR recombination → failure of thymocyte proliferation/V(D)J recombination → profound naive T-cell lymphopenia with restricted/oligoclonal TCR repertoire → SCID; residual autoreactive oligoclonal T-cell expansion with Th2 skewing → Omenn syndrome (erythroderma, eosinophilia, high IgE, hepatosplenomegaly, lymphadenopathy). (Demonstrated — PMID 38099988.) 4b. Neurodevelopmental branch: replication stress in neural progenitors → impaired neurogenesis → global developmental delay / progressive neurological regression. (Inferred by analogy to POLD1/POLD2; PMID 31449058.) 4c. Auditory/ectodermal branch: replication stress in cochlear and ectodermal (skin, hair, nail, dental enamel) progenitors → sensorineural hearing loss and ectodermal dysplasia-like features. (Inferred.)
  4. → Clinical syndrome: neonatal-onset syndromic SCID/Omenn with neurodevelopmental delay, deafness, and ectodermal/craniofacial anomalies; death in infancy/early childhood without—and sometimes despite—HSCT.

Supporting detail: - Molecular pathways/processes: DNA replication (GO:0006260), DNA repair / double-strand-break repair (GO:0006302), replication-stress / DNA-damage response via ATR–ATM–53BP1–RIF1, cell-cycle S-phase (GO:0000082), V(D)J recombination (GO:0033151), T-cell differentiation (GO:0030217), apoptosis (GO:0006915). Reactome: "DNA strand elongation," "Polymerase switching," "Lagging strand synthesis." KEGG: DNA replication (hsa03030), Base/Nucleotide excision repair, Mismatch repair. - Protein dysfunction: loss/reduction of function of the Pol δ accessory subunit; POLD3 also co-forms DNA polymerase ζ (translesion synthesis, with REV3L/REV7) and participates in break-induced replication/homologous recombination—so its loss broadly compromises genome maintenance. - Cellular processes: cell-cycle dysregulation (extended/arrested S phase), genomic instability, apoptosis of stressed progenitors. - Immune involvement: this is a primary immunodeficiency (combined T/B/NK), not autoimmunity per se—though Omenn physiology produces immune dysregulation/Th2 inflammation. - Cell types (CL): T cells (CL:0000084), naive T cell (CL:0000898), thymocyte (CL:0000893), double-positive thymocyte (CL:0000809), B cell (CL:0000236), natural killer cell (CL:0000623), hematopoietic stem cell (CL:0000037), neural progenitor/neuron (CL:0000031/CL:0000540), keratinocyte (CL:0000312). - Molecular profiling: no transcriptomic/proteomic/metabolomic datasets published for POLD3 patients; functional readouts to date are flow-cytometric immunophenotyping, TCR-repertoire sequencing, cell-cycle/EdU S-phase assays, and γH2AX DSB-foci quantification.

7. Anatomical Structures Affected

  • Organ level (primary): thymus (aplasia/hypoplasia, UBERON:0002370), bone marrow / hematopoietic system (UBERON:0002371), lymph nodes / spleen (lymphadenopathy, splenomegaly; UBERON:0000029/UBERON:0002106), brain / CNS (UBERON:0000955), inner ear / cochlea (UBERON:0001846/UBERON:0001844).
  • Secondary involvement: lungs/airways (recurrent infection, bronchiectasis; UBERON:0002048), liver (hepatomegaly; UBERON:0002107), skin (erythroderma, dryness; UBERON:0002097), hair follicles (alopecia), nails, teeth/enamel.
  • Body systems: immune/lymphatic, nervous, auditory, integumentary, respiratory (secondary), digestive (feeding difficulties).
  • Tissue/cell level: lymphoid tissue and lymphocyte progenitors; neural tissue; cochlear/sensory epithelium; ectodermal epithelia (epidermis, hair, nail matrix, ameloblasts).
  • Subcellular (GO Cellular Component): nucleus (GO:0005634), delta DNA polymerase complex (GO:0043625), zeta DNA polymerase complex (GO:0016035), replication fork (GO:0005657). POLD3 localizes to nucleus and cytoplasm (UniProt Q15054).
  • Lateralization: systemic/bilateral (e.g., bilateral sensorineural hearing loss); not lateralized.

8. Temporal Development

  • Onset: congenital/neonatal; immunologic and syndromic features manifest in early infancy. Onset pattern acute to subacute for infections (SCID presentation), with an insidious-progressive neurodevelopmental component.
  • Progression: rapid for the immune defect; progressive neurological regression (documented post-HSCT in the Omenn patient). Disease course is progressive, not relapsing/episodic.
  • Duration/stages: without curative therapy, SCID is fatal in the first 1–2 years; with HSCT, immune reconstitution is possible but non-immune (neuro/auditory) disease continues to progress → death reported at age 4 years despite HSCT at 6 months (PMID 38099988).
  • Remission patterns: no spontaneous remission; partial, compartment-specific improvement with HSCT (immune only).
  • Critical period / window of intervention: the neonatal–early-infancy window (ideally pre-infection HSCT, <3.5 months as in classic SCID) is critical for the immune compartment; however, the replication defect in CNS/cochlea likely has a developmental origin that transplantation cannot reverse.

9. Inheritance and Population

  • Inheritance: Autosomal recessive (biallelic/homozygous). Both reported families consanguineous.
  • Penetrance: presumed complete for biallelic pathogenic genotypes (n=2); expressivity variable between the two reports (classic SCID vs. Omenn presentation).
  • Anticipation: not applicable (not a repeat-expansion disorder). Germline mosaicism: not reported.
  • Founder effects / variant geography: both variants are private (one Lebanese, one in a separate pedigree reported from Europe); no founder haplotype established. Consanguinity (e.g., Middle Eastern/North African populations) increases the chance of homozygosity.
  • Carrier frequency: not established; both alleles are essentially absent from gnomAD, so heterozygous carriers are vanishingly rare.
  • Epidemiology: ultra-rare—only two patients reported worldwide (2023). Prevalence/incidence not quantifiable (far below 1/1,000,000). No sex predilection established (both reported probands male, but n too small to infer a sex ratio); AR inheritance predicts equal sex distribution. Age distribution: infants/young children.

10. Diagnostics

  • Laboratory tests:
  • Lymphocyte subsets by flow cytometry: low total/naive T cells (low TRECs), variable B and low NK cells; reduced naive CD4+/CD8+.
  • Immunoglobulins: low IgG, abnormal IgM, elevated IgE; eosinophilia (CBC with differential).
  • TCR-repertoire analysis: restricted/oligoclonal repertoire; evidence of defective early TCR recombination.
  • Biomarkers: no specific circulating biomarker; cellular replication-stress markers (γH2AX DSB foci; defective EdU/S-phase incorporation in patient fibroblasts) are diagnostic functional supports (PMID 38099988).
  • Imaging / functional: absent thymic shadow on chest imaging; audiometry/ABR for sensorineural hearing loss; brain MRI for neurodevelopmental assessment; chest CT for bronchiectasis.
  • Biopsy/pathology: Omenn skin shows erythroderma; lymphoid tissue shows oligoclonal T-cell infiltration (consistent with Omenn; general).
  • Genetic testing (diagnostic gold standard):
  • Whole-exome (WES) or whole-genome (WGS) sequencing identified both cases; IEI/SCID/combined-immunodeficiency NGS gene panels should include POLD1, POLD2, POLD3.
  • Single-gene/targeted confirmation and cascade/segregation testing in families; homozygosity mapping is useful in consanguineous pedigrees.
  • CMA/karyotype/FISH/mtDNA/repeat-expansion testing: not indicated (point-mutation disorder).
  • Clinical criteria / classification: meets SCID / Omenn syndrome diagnostic criteria (profound T-cell lymphopenia ± erythroderma, eosinophilia, high IgE, oligoclonal T cells); classified under IUIS "combined immunodeficiencies with associated/syndromic features."
  • Differential diagnosis: other SCID/Omenn genes—RAG1/RAG2, DCLRE1C (Artemis), LIG4, NHEJ1, DNA-PKcs/PRKDC, IL2RG, JAK3, IL7R, ADA, RMRP (cartilage-hair hypoplasia); and the related POLD1- and POLD2-deficiency syndromes (replication-stress CID; PMID 31449058). Distinguishing features: POLD3/POLD1/POLD2 disease uniquely couples SCID with replicative stress + neurodevelopmental delay + sensorineural hearing loss + ectodermal signs. Also distinguish POLD1 gain-of-function/MDPL (progeroid, mandibular hypoplasia, lipodystrophy) and POLD1/POLD2 proofreading-associated polyposis/cancer, which are mechanistically different and not part of IMD122.
  • Screening: detectable by newborn SCID screening (TREC assay) given profound T-cell lymphopenia; carrier/prenatal/PGT testing feasible once familial variant known.

11. Outcome / Prognosis

  • Survival/mortality: poor. SCID is fatal in infancy without HSCT; even with HSCT at 6 months, one patient died at age 4 years from progressive neurological regression (PMID 38099988). Disease-specific mortality is high.
  • Morbidity/disability: severe—recurrent/opportunistic infections, failure to thrive, developmental disability, sensorineural deafness, bronchiectasis (chronic lung damage).
  • Recovery potential: HSCT can reconstitute immunity (hematopoietic compartment) but does not correct the cell-intrinsic replication defect in CNS/cochlea/ectoderm, so neurodevelopmental and auditory outcomes remain poor.
  • Prognostic factors: age at HSCT, pre-transplant infection/organ damage, and—unique to this disorder—severity of the non-hematopoietic replication defect (neuro/auditory), which transplantation cannot rescue.
  • Prognostic biomarkers: degree of replication stress / genomic instability (γH2AX, S-phase defect) is a mechanistic correlate of severity (inferred).

12. Treatment

(No disease-specific approved therapy exists; management follows SCID/Omenn principles.)

  • Definitive: Allogeneic hematopoietic stem cell transplantation (HSCT) — NCIT:C15431 (Hematopoietic Stem Cell Transplantation) / NCIT:C105867 (Allogeneic HSCT). Reconstitutes the immune system; performed at 6 months in the reported Omenn patient (PMID 38099988). Does not address non-immune manifestations.
  • Supportive / prophylactic (standard SCID care, NCIT terms):
  • Immunoglobulin replacement therapy (IVIG/SCIG) — NCIT:C603 (Immunoglobulin Therapy).
  • Antimicrobial prophylaxis — anti-Pneumocystis (co-trimoxazole), antifungal, antiviral prophylaxis.
  • Irradiated, CMV-safe, leukodepleted blood products; avoidance of live vaccines.
  • Nutritional support for feeding difficulties; management of erythroderma; immunosuppression (e.g., steroids/cyclosporine) to control Omenn immune dysregulation pre-HSCT.
  • Rehabilitation: hearing aids/cochlear implantation, early developmental/physical/speech therapy, audiology follow-up.
  • Gene therapy / RNA / targeted / immunotherapy: none available or in trials for POLD3 deficiency. In vitro, WT POLD3 restoration rescues the cellular phenotype (PMID 38099988), providing proof-of-concept that gene correction could address the cell-intrinsic defect—experimental/hypothetical only.
  • Pharmacogenomics: none specific; standard transplant-conditioning pharmacogenetics (e.g., busulfan, thiopurines) apply generically. Caution with genotoxic conditioning/chemotherapy given underlying DNA-repair/replication fragility (inferred; analogous to other DNA-repair SCIDs such as Artemis/LIG4, where reduced-toxicity conditioning is preferred).
  • Clinical trials (NCT): none identified specific to POLD3/IMD122.

13. Prevention

  • Primary prevention: not preventable at the individual level (monogenic, congenital). Genetic counseling for consanguineous couples and families with an affected child (25% recurrence risk per pregnancy).
  • Secondary prevention / early detection: newborn SCID screening (TREC) enables presymptomatic detection and early pre-infection HSCT, the key opportunity to improve immune outcomes. Cascade testing of at-risk relatives.
  • Genetic/reproductive prevention: carrier screening, prenatal diagnosis, and preimplantation genetic testing (PGT-M) once the familial variant is known.
  • Tertiary prevention: infection prophylaxis, avoidance of live vaccines and non-irradiated blood products, early audiologic and developmental intervention, pulmonary care to limit bronchiectasis progression.
  • Immunization/public-health/environmental measures: not applicable beyond standard infection-control for immunocompromised infants.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: POLD3 is conserved across eukaryotes. Mouse Pold3 (NCBI Gene 69745; Mus musculus, NCBI:txid10090); orthologs in rat, zebrafish; the yeast functional homolog is POL32 (Saccharomyces cerevisiae). POLD3/POL32 is part of Pol δ and Pol ζ across species.
  • Natural disease in other species: no naturally occurring POLD3 disease reported in companion animals or wildlife (OMIA: none identified). Not a zoonosis; not transmissible.
  • Comparative biology: the replication/genome-maintenance function of POLD3/POL32 is deeply evolutionarily conserved, making model systems highly informative. Complete loss is lethal from yeast to mouse, underscoring essentiality.
  • Veterinary relevance: none established.

15. Model Organisms

  • Mouse (Mus musculus, Pold3):
  • Complete knockout (Pold3⁻/⁻) is embryonic lethal at E6.5 (PMID 29447390). "complete loss of Pold3 (Pold3-/-) resulted in early embryonic lethality at E6.5."
  • Inducible KO / blastocyst outgrowth / ESCs: rapid DNA-damage response, massive apoptosis, telomere loss, chromosome breaks, extended S phase, replicative stress, micronucleation, aneuploidy; Pold3 acts via 53BP1, RIF1, ATR, ATM.
  • Pold3⁺/⁻ (haploinsufficient) mice develop age-dependent impaired DSB repair, telomere shortening and chromosome breaks (spermatocytes).
  • Phenotype recapitulation: strongly models the cell-intrinsic replication-stress/genomic-instability mechanism of human disease; limitation: null is embryonic-lethal, so it cannot model the viable, organ-specific human syndrome—hypomorphic knock-in alleles (e.g., patient-equivalent) would be needed to recapitulate SCID + neuro/auditory features.
  • Cellular / in vitro models: patient-derived fibroblasts (S-phase defect, γH2AX DSB foci, rescued by WT POLD3 transduction — PMID 38099988); patient immune cells (TCR-repertoire/recombination assays). Yeast pol32Δ is a classic genetic model of the accessory subunit.
  • Other organisms: chicken DT40 and yeast systems have historically defined POLD3/POL32 roles in replication, translesion synthesis, and break-induced replication (background literature).
  • Resources: MGI (Pold3), IMPC/IMSR, Alliance of Genome Resources, SGD (POL32), Cellosaurus (patient fibroblast lines).

Supported vs. Refuted Hypotheses

Supported: - IMD122 is caused by autosomal-recessive, biallelic hypomorphic POLD3 missense variants (PMID 37030525; 38099988). - The mechanism is reduced Pol δ function → replicative stress / S-phase defect / DSB accumulation → impaired lymphopoiesis and TCR recombination → SCID/Omenn, with parallel injury to neural, cochlear, and ectodermal lineages (PMID 38099988; 29447390; 31449058). - POLD3 is essential and LoF-intolerant; only hypomorphic alleles are viable (gnomAD; mouse null lethality).

Refuted / excluded: - Not caused by environmental, infectious, or acquired/somatic factors; infections are a consequence. - Not a chromosomal/structural or repeat-expansion disorder. - IMD122 is distinct from POLD1 gain-of-function MDPL progeroid syndrome and from POLD1/POLD2 proofreading-associated polyposis/cancer.

Limitations and Future Directions

  • n=2 patients: frequencies, penetrance range, sex ratio, and full phenotypic spectrum are provisional; natural-history data are absent.
  • No omics (transcriptomic/proteomic/metabolomic) profiling, no registry, no clinical trials.
  • Unresolved: why certain tissues (cochlea, specific neural populations) are selectively vulnerable; whether reduced-toxicity HSCT conditioning improves outcomes; whether early gene-correction could rescue non-immune disease.
  • Future: patient-equivalent hypomorphic knock-in mouse models; iPSC-derived neural/cochlear organoids; identification of additional patients via GeneMatcher to define the phenotypic spectrum and genotype–phenotype correlations.

Key References

  • PMID 37030525 — Mehawej et al., 2023. POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment. (First case; p.Ile10Thr.)
  • PMID 38099988 — Riestra et al., 2023. Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome. (Second case; p.K373T; functional S-phase/DSB rescue.)
  • PMID 31449058 — Conde et al., 2019 (J Clin Invest). Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. (POLD1/POLD2 parent syndrome.)
  • PMID 29447390 — Zhou et al., 2018. Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis. (Mouse model.)
  • Database sources: OMIM 620869; MONDO:0971151 (Monarch); UniProt Q15054; gnomAD (POLD3 constraint); HPO annotations (OMIM 620869).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 70
Resolved 68
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 4
Terms named correctly 0
Terms named as a different term 2
Terms whose name is worth a second look 2

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:

  • MONDO:0971151 (3 mentions) - the report calls it "Monarch"; MONDO calls it immunodeficiency 122
  • NCIT:C603 (1 mention) - the report calls it "Immunoglobulin Therapy"; NCIT calls it Isotretinoin

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0002371 (1 mention) - the report calls it "bone marrow / hematopoietic system"; UBERON calls it bone marrow
  • UBERON:0000955 (1 mention) - the report calls it "brain / CNS"; UBERON calls it brain

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.