Immunodeficiency 96

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Classifications

Harrison's Part

IUIS Category

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Mappings

NCIT

NCIT:C122658 DNA Ligase I Deficiency

NCI Thesaurus carries the disease under its enzyme-deficiency name rather than under the OMIM numbering, but it denotes the same entity: inherited deficiency of DNA ligase I. exactMatch rather than closeMatch because neither term is narrower than the other - "immunodeficiency 96" and "DNA ligase I deficiency" are the OMIM and enzymological names for one disease.

NCIT

NCIT:C122658 DNA Ligase I Deficiency

NCI Thesaurus carries the disease under its enzyme-deficiency name rather than under the OMIM numbering, but it denotes the same entity: inherited deficiency of DNA ligase I. exactMatch rather than closeMatch because neither term is narrower than the other - "immunodeficiency 96" and "DNA ligase I deficiency" are the OMIM and enzymological names for one disease.

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Inheritance

1

Autosomal recessive HP:0000007

Every reported patient carries two LIG1 variants, either compound heterozygous or homozygous in consanguineous kindreds; heterozygous parents and siblings are unaffected, although heterozygous cells show intermediate damage responses in vitro.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity."

States the autosomal recessive, partial (hypomorphic) nature of the disease-causing genotypes.

PMID:35748970 SUPPORT Other

"Ligase I deficiency LIG1 AR 126391 Lymphopenia,"

The IUIS row records the gene, the autosomal recessive inheritance mode and the OMIM gene entry for DNA ligase I deficiency.

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Mechanistic Hypotheses

1

Lymphoid precursors fail because they divide fastest, not because LIG1 has an immune-specific role

proliferative_exposure_lymphoid_selectivity EMERGING

Evidence balance 2 support

The dominant explanation in the literature for why a ubiquitous replicative ligase defect presents as an immunodeficiency is that lymphocyte precursors are among the most rapidly proliferating cells in the body and therefore the most exposed to an unrepaired lagging-strand lesion. The competing possibility - that LIG1 has a specific role in an immune-restricted process such as somatic hypermutation or alpha-beta/gamma-delta lineage commitment - is raised by the same series, which found reduced somatic hypermutation and a gamma-delta expansion that pure proliferative exposure does not obviously explain. Neither has been tested against the other.

Show evidence (2 references)

PMID:38896336 SUPPORT Human Clinical

"Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"

States the proliferative-exposure hypothesis in the source's own words, as an inference from the clinical pattern rather than as a tested result.

PMID:30395541 SUPPORT Human Clinical

"Mutation extent was significantly reduced in P1, suggest - ing that LIG1 has a greater role during somatic hypermutation than previously known."

The competing possibility: a specific LIG1 role in an immune-restricted process. Recorded here because it is what keeps the hypothesis EMERGING rather than settled. The quote preserves the source PDF's "suggest-|ing" line-break hyphenation.

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Discussions and Knowledge Gaps

5

By what mechanism does a general defect in replicative DNA ligation produce an immunodeficiency, when the paralogous LIG4 deficiency has a clean explanation in failed V(D)J recombination?

KNOWLEDGE GAP OPEN lig1_immunodeficiency_mechanism_unknown

Attached to

pathophysiology#Impaired Lymphocyte Development and Proliferation pathophysiology#Genomic Instability and Hypersensitivity to DNA-Damaging Agents

This is the central open question of the disease and the reason the edge from the cellular damage phenotype to the lymphoid phenotype is drawn as indirect with unknown intermediates. LIG1 is required in every dividing cell, yet the clinical picture is dominated by lymphoid failure with comparatively little else. The proliferative-exposure argument is plausible but has never been tested against the alternative that LIG1 serves an immune-restricted function, and a 2020 review of the ligase deficiency syndromes states flatly that the cause is not known.

Show evidence (1 reference)

PMID:31630206 SUPPORT Other

"In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known."

States the gap directly, and contrasts it with the paralogous disease where the mechanism is established.

Is reduced catalytic efficiency sufficient to cause LIG1 syndrome, or is abortive ligation - the release of an adenylated intermediate that other ligases cannot then act on - the necessary defect?

KNOWLEDGE GAP OPEN lig1_which_biochemical_defect_causes_disease

Attached to

pathophysiology#Abortive Ligation and Accumulation of Adenylated DNA

The two known pathogenic alleles, R641L and R771W, have both defects at once, so nothing in the patient data separates them. The question became answerable in 2024 when three further rare LIG1 variants were characterised: R305Q and R768W lower catalytic efficiency without elevated abortive ligation, and R641S does both more severely than R641L. If carriers of the abortive-ligation-sparing alleles turn out not to have immune disease, the abortive intermediate is the pathogenic lesion. This bears directly on whether aprataxin or FEN1 activity would modify severity, which the 2018 series proposed but could not test.

Show evidence (1 reference)

PMID:39510190 SUPPORT In Vitro

"In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency."

States the gap in the exact terms it is posed here, and identifies the variant set that could resolve it.

Is complete biallelic LIG1 loss lethal in humans, or simply not yet ascertained?

OPEN QUESTION OPEN lig1_null_lethality_untested

Attached to

pathophysiology#Biallelic Hypomorphic LIG1 Variants

Every published patient retains residual activity on at least one allele, and the field reads that as evidence that a true null is incompatible with life. The inference is reasonable but the sample is eight people, and the counter-evidence is not trivial. Cells lacking LIG1 remain viable because the other ligases compensate; mice homozygous for the human R771W allele keep normal haematopoiesis; and Lig1-null mouse cells actually outperform a human LIG1 point mutant in survival and replication assays, which points the wrong way for a simple dose model and suggests instead that a crippled ligase occupying the nick is worse than none at all. Against that, the mouse null is embryonic-lethal in mid-gestation from a haematopoietic proliferative defect, which is the strongest single piece of support for human null-lethality. The claim as stated is an ascertainment argument, and this entry records it as one rather than as an established fact.

Show evidence (4 references)

PMID:38896336 SUPPORT Human Clinical

"Intriguingly, all reported LIG1 patients have at least one hypomorphic allele that preserves some residual function, suggesting that full loss of function may be incompatible with life."

States the inference and, in the word "suggesting", its epistemic status.

PMID:11896201 SUPPORT Model Organism

"Our previous finding that Lig1 knockout mouse embryos developed normally to mid-term before succumbing to a specific haematopoietic defect was difficult to reconcile with a report that DNA ligase I is essential for the viability of cultured mammalian cells."

Supports the lethality side of the question: a complete null is embryonic-lethal in mouse, from a haematopoietic defect.

PMID:11896201 REFUTE In Vitro

"Lig1 null mouse cells performed better in the survival and replication assays than a human LIG1 point mutant, and we suggest that the complete absence of DNA ligase I may make it easier for another ligase to compensate for DNA ligase I deficiency."

Cuts against the assumption that a null is necessarily worse than a hypomorph: at the cellular level the null is the milder state, because absence of the protein permits compensation that a defective protein blocks.

+ 1 more reference

Why does the anemia persist after haematopoietic stem cell transplantation in some patients despite adequate lymphoid engraftment?

KNOWLEDGE GAP OPEN lig1_persistent_anemia_after_transplant

Attached to

pathophysiology#Impaired Erythroid DNA Synthesis treatments#Haematopoietic stem cell transplantation

Two transplanted patients remained transfusion-dependent or anemic with good lymphoid but poor myeloid chimerism. If the erythroid defect is cell-intrinsic to haematopoietic progenitors, as the proposed mechanism for the macrocytosis implies, then incomplete myeloid engraftment is a sufficient explanation and the remedy is a conditioning regimen that clears more host marrow. But conditioning intensity is exactly what the cellular radiosensitivity constrains, so the two requirements pull against each other. No study has addressed this, and one family declined the second transplant that would have tested it.

Show evidence (1 reference)

PMID:36341401 SUPPORT Other

"Macrocytic anemia probably results from an impaired DNA synthesis in hematopoietic precursor cells"

Supports the cell-intrinsic-progenitor premise of the question; the same report documents the persistent transfusion dependence after transplant.

Do individuals with LIG1 deficiency carry an increased lifetime cancer risk, and does it warrant surveillance?

OPEN QUESTION OPEN lig1_cancer_risk_uncharacterised

Attached to

phenotypes#Lymphoma

A genome-instability disorder with radiosensitivity would be expected to predispose to malignancy, and there are two supporting observations: the 1992 index patient had lymphocytic liver infiltrates suggestive of lymphoma at death aged 19, and aged Lig1 R771W mice develop an excess of spontaneous tumours. Against that, no malignancy has been reported in any of the seven later patients, all of whom are alive and most of whom are under ten years old - so the cohort has neither the size nor the follow-up to detect a real risk. No surveillance recommendation exists and none is asserted here.

Show evidence (2 references)

PMID:1351188 SUPPORT Human Clinical

"A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."

The single reported human malignancy, and the reason the question is open rather than closed.

PMID:30725883 SUPPORT Other

"Other rare syndromes include ataxia telangiectasia-like disorder; immunodeficiency, centromeric instability, and facial anomalies syndromes; Cockayne syndrome; trichothiodystrophy; xeroderma pigmentosum; DNA ligase I deficiency; PMS2 deficiency; and DNA recombinase repair defects..."

Places DNA ligase I deficiency in the chromosomal instability syndrome family, whose members are characteristically associated with malignancy risk. This is the class-membership argument for asking the question, not evidence of risk in this disease.

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Pathophysiology

8

Biallelic Hypomorphic LIG1 Variants

Two LIG1 alleles of reduced function. The allelic spectrum runs from frameshift alleles that delete the entire catalytic core (T415Mfs*10, P260*) through active-site and DNA-binding missense alleles of graded severity (E566K, R771W, R641L, A624T). Crucially the two alleles are never both null: every reported genotype retains residual catalytic activity, which the field reads as evidence that complete LIG1 loss is not compatible with life.

LIG1 hgnc:6598 ↓ DECREASED

Genetic context variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: SPLICE_SITE_VARIANT functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Biallelic germline LIG1 alleles, compound heterozygous in the non-consanguineous kindreds and homozygous in the consanguineous ones. Recorded as PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION because the disease state is necessarily a partial one - a genotype with no residual ligase activity has never been observed in a patient.

DNA ligase (ATP) activity GO:0003910 ↓ DECREASED

Downstream

Impaired Okazaki Fragment Ligation Reduced ligase activity leaves lagging-strand nicks unsealed. The 46BR fibroblast strain from the index patient demonstrated this directly: retarded joining of Okazaki fragments alongside the ligase defect.

Abortive Ligation and Accumulation of Adenylated DNA Two of the patient alleles do not simply ligate more slowly - they transfer AMP to the nick and then release the intermediate before sealing it, which is a distinct biochemical lesion from reduced turnover.

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1."

Establishes the biallelic LIG1 genotype as the initiating lesion in the disease-defining series.

PMID:38896336 SUPPORT Human Clinical

"Intriguingly, all reported LIG1 patients have at least one hypomorphic allele that preserves some residual function, suggesting that full loss of function may be incompatible with life."

Supports recording the impact as partial rather than complete loss of function: no observed genotype is a double null.

Impaired Okazaki Fragment Ligation

LIG1 seals the nick between adjacent Okazaki fragments on the lagging strand, a step repeated tens of millions of times per replication cycle. With reduced ligase activity these nicks persist, so the lagging strand leaves S phase discontinuous.

Okazaki fragment processing GO:0033567 ↓ DECREASED

Downstream

Persistent Single-Strand Nicks and Replication-Associated DNA Breaks

Show evidence (2 references)

PMID:1581963 SUPPORT In Vitro

"These cells exhibit retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents."

Demonstrates retarded Okazaki-fragment joining in patient-derived fibroblasts carrying the LIG1 mutations.

PMID:38896336 SUPPORT Other

"LIG1 is the most critical ligase for DNA replication, connecting over 50 million Okazaki fragments during every replication cycle"

Quantifies the scale of the ligation burden that this node describes, which is why a partial activity loss is not buffered.

Abortive Ligation and Accumulation of Adenylated DNA

A lesion specific to certain LIG1 alleles, and not the same thing as being slow. R641L and R771W bind Mg2+ poorly, catalyse adenylyl transfer to the nick, then dissociate before sealing it. Because LIG1 is immediately re-adenylylated it cannot rebind the intermediate, so the abortive product is a 5'-adenylated nick that only aprataxin or flap-displacement synthesis can clear. It therefore blocks the very lesion it was meant to repair.

DNA ligase (ATP) activity, aborting after adenylyl transfer GO:0003910 ⚠ ABNORMAL

Downstream

Persistent Single-Strand Nicks and Replication-Associated DNA Breaks

Show evidence (2 references)

PMID:30395541 SUPPORT In Vitro

"Under these conditions, R641L and R771W underwent abortive ligation approximately 50% of the time, compared with less than 1% for WT and the P529L variant"

Quantifies abortive ligation for the two patient alleles at physiological ATP and Mg2+ against wild-type and against the neutral P529L allele.

PMID:39510190 SUPPORT In Vitro

"In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency."

Confirms abortive ligation as a distinct biochemical defect of the patient alleles, and records that its individual sufficiency for disease is open.

Persistent Single-Strand Nicks and Replication-Associated DNA Breaks

Unsealed nicks from replication and from unfinished excision repair persist into and beyond S phase. Encountered by a replication fork, a single-strand nick is converted into a one-ended double-strand break, which is why cells with a purely ligation-level defect show gamma-H2AX foci - a double-strand-break marker - both at baseline and after irradiation.

single strand break repair GO:0000012 ↓ DECREASED base-excision repair GO:0006284 ↓ DECREASED

Animal models

Lig1 null mouse Mouse recapitulates Null fibroblasts show the accumulation of unfinished replication intermediates and the resulting genome instability that this node asserts.

Downstream

Genomic Instability and Hypersensitivity to DNA-Damaging Agents The unusual feature of this step is that the instability is attributed to the replication defect itself rather than to a co-existing repair failure. Lig1-null mouse cells have no demonstrable repair deficiency and are still genomically unstable, which is what the source's "unusually" is doing.

Show evidence (2 references)

PMID:38896336 SUPPORT In Vitro

"Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."

Shows that patient cells carry an elevated baseline burden of DNA damage, not merely an impaired response to an applied insult.

PMID:36341401 SUPPORT Other

"As result, Okazaki fragments are improperly catalyzed during cell replication and single-strand DNA damage repair."

States the dual replicative and single-strand-repair consequence that this node represents.

Genomic Instability and Hypersensitivity to DNA-Damaging Agents

The cellular signature of the disease: patient fibroblasts and EBV-transformed B cells lose viability after alkylating agents and after ionizing radiation, and patient T cells accumulate excess gamma-H2AX after irradiation. Heterozygous relatives show an intermediate response, which is a dose effect rather than a threshold one.

B cell CL:0000236 T cell CL:0000084

cellular response to DNA damage stimulus GO:0006974 ⚠ ABNORMAL

Downstream

Impaired Lymphocyte Development and Proliferation Recorded as having unknown intermediates on purpose. That LIG1-deficient lymphocytes handle DNA damage badly is established; the steps from that to a lineage-weighted developmental failure are not, and a review of the ligase deficiency syndromes states outright that the cause of the immunodeficiency in DNA ligase I deficiency is unknown.

Impaired Erythroid DNA Synthesis

Somatic Hypermutation Defect

Show evidence (2 references)

PMID:30395541 SUPPORT In Vitro

"These data indicate that both B and T cells demonstrate a decreased capacity to respond to chemical and radiation-induced DNA damage."

Establishes the damage-response defect in the two lymphocyte lineages that carry the clinical phenotype.

PMID:1581963 SUPPORT In Vitro

"These cells exhibit retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents."

The original demonstration of broad DNA-damage hypersensitivity in LIG1-mutant patient cells.

Impaired Lymphocyte Development and Proliferation

The lymphoid compartment is hit hardest, which is the observation the literature explains by lymphocyte precursors being among the most rapidly dividing cells in the body and therefore the most exposed to a replicative ligation defect. Patients show reduced T and B cell counts, depressed proliferation to mitogen, and a relative expansion of gamma-delta T cells.

B cell CL:0000236 T cell CL:0000084

lymphocyte proliferation GO:0046651 ↓ DECREASED B cell differentiation GO:0030183 ↓ DECREASED T cell differentiation GO:0030217 ⚠ ABNORMAL

Animal models

Lig1 R771W knock-in mouse Mouse fails to recapitulate Mice homozygous for the same substitution that causes human disease keep their haematopoietic lineages intact, so the central human lesion is not reproduced.

Lig1 null mouse Mouse partially recapitulates The null embryo's lethal lesion is haematopoietic and proliferative, which matches the proposed mechanism for the human lymphoid failure. It is only a partial match because the mouse defect is quantitative across the whole haematopoietic compartment with no lineage specificity, whereas the human disease is lymphoid-weighted.

Downstream

Hypogammaglobulinemia

Decreased total lymphocyte count

Increased gamma-delta T cell proportion The gamma-delta expansion is proportional rather than absolute and its mechanism is a hypothesis in the source, not a demonstrated step: either failed commitment of precursors to the alpha-beta lineage or inefficient recombination at the alpha-beta locus.

Show evidence (2 references)

PMID:38896336 SUPPORT Human Clinical

"Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"

States both the lymphoid phenotype and the proliferative-exposure argument that this node rests on.

PMID:30395541 SUPPORT Human Clinical

"We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"

Reports the T-lymphopenia-with-gamma-delta-expansion pattern in every patient of the defining series.

Somatic Hypermutation Defect

A B-cell-intrinsic finding separate from the numerical B cell defect. Sequencing of VH3 clones from one patient showed both fewer mutated clones and a smaller extent of mutation per clone than in parents, siblings or controls - a role for LIG1 in somatic hypermutation that was not previously recognised. This is a single-patient result and is curated as such.

B cell CL:0000236

somatic hypermutation of immunoglobulin genes GO:0016446 ↓ DECREASED

Downstream

Hypogammaglobulinemia

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Mutation extent was significantly reduced in P1, suggest - ing that LIG1 has a greater role during somatic hypermutation than previously known."

Reports the reduced extent of somatic hypermutation in the patient studied and the authors' inference about LIG1's role. The quote preserves the source PDF's "suggest-|ing" line-break hyphenation.

Impaired Erythroid DNA Synthesis

Erythroid precursors cannot replicate DNA fast enough relative to cytoplasmic maturation, giving the megaloblastic-type dissociation that produces large red cells. The mechanism is proposed rather than demonstrated: the 2018 series says the exact mechanism is not clear and offers slowed DNA synthesis as the explanation, which is the standard route to macrocytosis.

erythroid progenitor cell CL:0000038

erythrocyte differentiation GO:0030218 ⚠ ABNORMAL

Downstream

Increased mean corpuscular volume

Macrocytic anemia

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"LIG1 deficiency may lead to increased erythro - cyte size through failure to produce DNA quickly enough during replication."

The proposed mechanism for the macrocytosis, stated by the source as a possibility. The quote preserves the source PDF's "erythro-|cyte" line-break hyphenation.

PMID:36341401 SUPPORT Other

"Macrocytic anemia probably results from an impaired DNA synthesis in hematopoietic precursor cells"

An independent statement of the same proposed mechanism, and the reason this node is separated from the lymphoid arm.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

18

Blood 10

Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313

Sequelae: Recurrent infections

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."

Reports hypogammaglobulinemia as one of the four defining laboratory features of the series.

PMID:38896336 SUPPORT Human Clinical

"Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."

Independent confirmation in a patient with a different genotype, and the severe (pan-hypogammaglobulinemic) end of the range.

Decreased total lymphocyte count HP:0001888

Sequelae: Recurrent infections

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."

Reports lymphopenia among the defining laboratory features.

PMID:35748970 SUPPORT Other

"Ligase I deficiency LIG1 AR 126391 Lymphopenia,"

The IUIS row records lymphopenia as the T-cell column entry for DNA ligase I deficiency.

Decreased total T cell count HP:0005403

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"

Reports T cell lymphopenia in all patients of the defining series.

Decreased total B cell count HP:0010976

Show evidence (1 reference)

PMID:38896336 SUPPORT Human Clinical

"Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"

Records decreased B cell counts as part of the established clinical picture of LIG1 deficiency.

Increased gamma-delta T cell proportion HP:0500270

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."

Reports the increased gamma-delta T cell proportion as a defining feature.

PMID:36341401 SUPPORT Human Clinical

"Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy."

Independent statement that the gamma-delta expansion is among the most common manifestations of the disease.

Decreased mitogen-induced T-cell proliferation HP:0031381

Show evidence (2 references)

PMID:38896336 SUPPORT Human Clinical

"Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."

Reports the diminished mitogen response directly.

PMID:35748970 SUPPORT Other

"Ligase I deficiency LIG1 AR 126391 Lymphopenia,"

The IUIS T-cell column for Ligase I deficiency reads "Lymphopenia, increased gamma-delta T cells, decreased mitogen response"; this quote is the resolvable leading substring of that cell.

Macrocytic anemia HP:0001972

Show evidence (1 reference)

PMID:36341401 SUPPORT Human Clinical

"Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy."

Lists macrocytic anemia among the most common manifestations of the disease.

Increased mean corpuscular volume HP:0005518

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"

States that red cell macrocytosis is shared by every reported patient, which is why it is curated separately from the anemia.

Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:38896336 SUPPORT Human Clinical

"Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."

Reports neutropenia in the patient with the homozygous A624T genotype.

Lymphoma HP:0002665

Show evidence (1 reference)

PMID:1351188 SUPPORT Human Clinical

"A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."

The single reported human lymphoma in this disease, in the index patient.

Cardiovascular 1

Conjunctival telangiectasia HP:0000524

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Hepatosplenomegaly; bronchiectasis; ocular telangiectasia; sun sensitivity;"

The complications cell of the clinical table for the index patient, listing ocular telangiectasia.

Genitourinary 1

Multicystic kidney dysplasia HP:0000003

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Both were diagnosed as infants with SCID, complicated by multicystic dysplastic kidneys and severe anemia requiring blood transfusions."

Reports multicystic dysplastic kidneys in the two brothers at the severe end of the defining series.

Immune 2

Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:35748970 SUPPORT Other

"Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells"

The IUIS associated-features cell lists recurrent bacterial and viral infections first among the clinical manifestations.

Eczematoid dermatitis HP:0000964

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Severe eczema; severe anemia; no dysmorphia"

The complications cell of the clinical table for the patient in whom severe eczema was recorded.

Integument 1

Cutaneous photosensitivity HP:0000992

Show evidence (1 reference)

PMID:1351188 SUPPORT Human Clinical

"A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."

Records sun sensitivity in the index patient in whom LIG1 mutations were first identified.

Respiratory 1

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Hepatosplenomegaly; bronchiectasis; ocular telangiectasia; sun sensitivity;"

The complications cell of the clinical table for the index patient, listing bronchiectasis.

Cellular 1

Increased sensitivity to ionizing radiation HP:0011133

Show evidence (2 references)

PMID:36341401 SUPPORT In Vitro

"Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"

Reports the clonogenic-survival result in patient fibroblasts and its intermediate position relative to an Artemis-deficient comparator.

PMID:38896336 SUPPORT In Vitro

"Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."

Independent demonstration of DNA-damage hypersensitivity in patient fibroblasts with a different genotype.

Growth 1

Growth delay HP:0001510

Show evidence (2 references)

PMID:1351188 SUPPORT Human Clinical

"A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."

Records growth retardation in the index patient.

PMID:35748970 SUPPORT Other

"Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells"

Growth retardation is listed among the IUIS associated features for Ligase I deficiency.

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Genetic Associations

1

LIG1

Gene: LIG1 hgnc:6598 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:30395541 SUPPORT Human Clinical

"We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1."

Establishes LIG1 as the causal gene in the disease-defining series.

PMID:30395541 SUPPORT In Vitro

"The R771W missense mutation exhibits only 4.5% of WT activity"

Quantifies the residual activity of the most frequently reported patient allele, which is the basis for calling the genotypes hypomorphic.

PMID:39510190 SUPPORT In Vitro

"Hypomorphic LIG1 variants R771W and R641L cause immune deficiencies in LIG1 Syndrome patients."

Independent confirmation of the gene-disease relationship and of the hypomorphic allele architecture.

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Variants

4

LIG1 p.Arg771Trp (R771W) Pathogenic

Gene: LIG1 hgnc:6598 SNV

The recurrent allele of this disease: present in the 1992 index patient (heterozygous), homozygous in all three members of kindred C, and hit at the same codon by a different substitution (R771G) in the 2022 Omenn-like patient. R771 sits next to a DNA-binding motif in the OB-fold domain, and the substitution both lowers catalytic activity to about 4.5% of wild type and weakens Mg2+ affinity, causing abortive ligation about half the time at physiological Mg2+. CADD 34; ExAC minor allele frequency 0.00005.

Show evidence (2 references)

PMID:30395541 SUPPORT In Vitro

"The R771W missense mutation exhibits only 4.5% of WT activity"

Quantifies the residual catalytic activity of this allele.

PMID:30395541 SUPPORT In Vitro

"Under these conditions, R641L and R771W underwent abortive ligation approximately 50% of the time, compared with less than 1% for WT and the P529L variant"

Documents the abortive-ligation defect of this allele at physiological ATP and Mg2+ concentrations.

LIG1 p.Arg641Leu (R641L) Pathogenic

Gene: LIG1 hgnc:6598 SNV

Carried in compound heterozygosity with T415Mfs*10 by two unrelated White patients from different countries who nonetheless shared both alleles; haplotype analysis found no founder effect, so the pair arose independently. R641 lies in a hairpin loop that contacts the minor groove of nicked DNA and forms a salt bridge with D600; replacing it with leucine leaves about 7% of wild-type activity and, like R771W, produces abortive ligation at physiological Mg2+. These two patients occupy the mild end of the clinical spectrum.

Show evidence (1 reference)

PMID:30395541 SUPPORT In Vitro

"whereas the R641L substitution demonstrates an estimated 7% of WT activity"

Quantifies the residual catalytic activity of this allele.

LIG1 p.Thr415MetfsTer10 (T415Mfs*10) Pathogenic

Gene: LIG1 hgnc:6598 INDEL

A frameshift introducing a premature stop and removing the entire catalytic core, expressed only at very low levels as a truncated protein. It is the closest thing to a null allele in the reported spectrum, and it is never seen with a second severe allele - both carriers pair it with R641L.

Show evidence (1 reference)

PMID:30395541 SUPPORT In Vitro

"We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA."

Supports classifying the patient allele set as containing amorphic as well as hypomorphic members; T415Mfs*10 is the amorphic one.

LIG1 p.Ala624Thr (A624T) Pathogenic

Gene: LIG1 hgnc:6598 SNV

Homozygous in a consanguineous Saudi patient with SCID. Its interest is mechanistic rather than clinical: it lowers Mg2+ affinity 2.5-fold and, by an allosteric effect on the high-fidelity Mg2+ site, raises ligation fidelity more than 50-fold against 3'-8-oxoguanine mismatches. Higher fidelity is not a benefit here - it means the enzyme refuses to process the nicks it encounters, converting them into persistent single- and double-strand breaks. This is the one allele where a gain in one enzymatic property is part of the disease mechanism.

Show evidence (2 references)

PMID:38896336 SUPPORT Human Clinical

"Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."

Establishes the genotype and the clinical phenotype it produced.

PMID:38896336 SUPPORT In Vitro

"The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold."

Quantifies the magnesium-affinity defect that underlies the reduced activity of this allele.

💊

Medical Actions

5

Immunoglobulin replacement therapy

Action: immunoglobulin replacement therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

The mainstay for every reported patient, before and after any transplant. Intravenous or weekly subcutaneous. Note that it remains necessary after transplantation in the patients with poor B-cell engraftment, so it is not a bridge to transplant but a parallel therapy.

Mechanism Target:

Hypogammaglobulinemia — Replaces the missing antibody rather than correcting the ligase defect, so it addresses the humoral consequence and nothing upstream of it.

Show evidence (2 references)

PMID:30395541 SUPPORT Human Clinical

"Lacking a specific genetic diagnosis, each was diagnosed with a form of common variable immune deficiency (CVID), and has been treated with replace - ment immunoglobulin."

Documents immunoglobulin replacement as the treatment given to the milder patients. The quote preserves the source PDF's "replace-|ment" line-break hyphenation.

PMID:38896336 SUPPORT Human Clinical

"She is maintained on weekly subcutaneous immunoglobulin therapy."

Records continued subcutaneous immunoglobulin six years after transplantation, which is the basis for saying it is not merely a bridge.

Haematopoietic stem cell transplantation

Action: haematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only treatment that addresses the haematopoietic arm of the disease, and it has been used in four of the eight reported patients, at ages from four months to three years. Outcomes are mixed in an informative way: lymphoid engraftment has been good, myeloid engraftment poor or absent in three of the four, and two patients remained transfusion-dependent afterwards. It does not address the non-haematopoietic consequences of a defect that is present in every cell. Conditioning intensity is constrained by the cellular radiosensitivity and alkylator hypersensitivity, and reduced-intensity regimens or no conditioning at all have been used.

Mechanism Target:

Impaired Lymphocyte Development and Proliferation — Replaces the LIG1-deficient haematopoietic compartment with donor cells that carry functional ligase, so the lymphoid arm can be reconstituted. Non-haematopoietic tissues keep the patient genotype.

Show evidence (3 references)

PMID:30395541 SUPPORT Human Clinical

"Both patients were treated with hematopoietic stem cell transplantation."

Records transplantation in the two brothers at the severe end of the 2018 series.

PMID:36341401 SUPPORT Human Clinical

"Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol."

Documents transplantation with a reduced-intensity protocol in the Omenn-like patient.

PMID:38896336 SUPPORT Human Clinical

"The patient received hematopoietic stem cell transplantation (HSCT) from her HLA-matched sister without conditioning at the age of 6 months."

Records an unconditioned matched-sibling transplant, the least intensive approach reported, in a patient whose cells are radiosensitive.

Antimicrobial prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: antibacterial, antiviral, antifungal and anti-Pneumocystis prophylaxis NCIT:C254

Platform: Small molecule

Antibiotic prophylaxis alongside immunoglobulin replacement in the patient maintained without transplantation, and anti-viral, anti-fungal and anti-Pneumocystis prophylaxis in the infant with SCID before transplant. Recorded as documented management; no reported patient series measures its effect separately from immunoglobulin.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"she is not so profoundly T cell lymph- openic and is maintained on immune globulin replacement and antibiotics"

Documents ongoing antibiotic prophylaxis alongside immunoglobulin in the untransplanted member of kindred C. The quote preserves the source PDF's "lymph-|openic" line-break hyphenation.

Red blood cell transfusion

Action: red blood cell transfusion Ontology label: Packed Red Blood Cell Transfusion NCIT:C15409

Platform: Other

Supportive treatment for the anemia, needed repeatedly in three patients - approximately every two weeks in the Omenn-like infant - and still needed after transplantation in two. Its persistence post-transplant is why one family was offered a second transplant. Transfused products were irradiated and filtered in the reported case.

Mechanism Target:

Macrocytic anemia — Replaces circulating red cells; it does nothing to the erythroid progenitor defect that generates them.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Both were diagnosed as infants with SCID, complicated by multicystic dysplastic kidneys and severe anemia requiring blood transfusions."

Records transfusion dependence in the two most severely affected patients of the defining series.

Genetic counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal recessive with a 25% sibling recurrence risk. Relevant in practice because two of the three kindreds in the defining series were consanguineous, and because the second reported family reached diagnosis only after an affected cousin was recognised.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity."

Establishes the autosomal recessive inheritance that the counselling addresses. Note that the same source also establishes the variability, which is what makes prognostic counselling hard.

🌍

Environmental Factors

2

Exposure to ionizing radiation

Not a cause of the disease, which is entirely germline, but a modifier of its cellular pathology with direct clinical consequences. Patient fibroblasts and lymphoblastoid lines lose viability after irradiation and accumulate excess gamma-H2AX foci. In practice this constrains transplant conditioning intensity - reduced-intensity and unconditioned regimens have been used - and argues for caution with diagnostic and therapeutic radiation.

Show evidence (1 reference)

PMID:36341401 SUPPORT In Vitro

"Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"

Records the measured radiosensitivity of patient-derived cells that this exposure entry is about.

Mechanism Target:

EXACERBATES Genomic Instability and Hypersensitivity to DNA-Damaging Agents — Irradiation adds strand breaks to a cell that already cannot seal the ones it generates itself, so the damage burden this node describes rises.

Show evidence (1 reference)

PMID:38896336 SUPPORT In Vitro

"Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."

Demonstrates that an applied genotoxic insult worsens an already elevated baseline damage burden in patient cells.

Exposure to ultraviolet radiation

Sunlight exposure in a cell that cannot complete nucleotide excision repair. This is the exposure behind the sun sensitivity of the index patient, and it supports sun protection as management, though the phenotype is variable and was not reported in the 2018 series.

Show evidence (1 reference)

PMID:1351188 SUPPORT Human Clinical

"A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."

Records the clinical sun sensitivity that identifies UV as a relevant exposure in this disease.

Mechanism Target:

EXACERBATES Genomic Instability and Hypersensitivity to DNA-Damaging Agents — UV lesions are repaired by excision pathways whose final step LIG1 performs, so an unrepaired UV burden adds to the same pool of unsealed nicks.

Show evidence (1 reference)

PMID:1581963 SUPPORT In Vitro

"The data indicate that human DNA ligase I is required for joining of Okazaki fragments during lagging-strand DNA synthesis and the completion of DNA excision repair."

Establishes LIG1's requirement for completing excision repair, which is the pathway that clears UV photoproducts and the basis for this edge.

🔬

Biochemical Markers

2

Serum immunoglobulins

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."

Establishes hypogammaglobulinemia as a measured feature of the cohort.

Mean corpuscular volume

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"

Supports treating raised MCV as the near-universal biochemical marker of the disease.

🔬

Diagnosis

4

Lymphocyte subset immunophenotyping with gamma-delta T cell fraction

Flow cytometry is the entry point, and the discriminating measurement is not the absolute lymphocyte count but the gamma-delta fraction of CD3+ T cells. An elevated gamma-delta proportion in a hypogammaglobulinemic child narrows the differential to the DNA repair defects and hypomorphic RAG, and away from LIG4 deficiency, where it is not reported.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"

Establishes the combination of T lymphopenia with a raised gamma-delta fraction as present in every patient, which is what makes it useful.

Full blood count with red cell indices

Raised MCV is the cheapest pointer to this diagnosis and is present even where the immune phenotype is mild. The trap it sets is a nutritional one: two of the reported patients were worked up for transcobalamin II deficiency on the strength of the macrocytosis before genetic testing.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"

Supports red cell indices as a near-universally abnormal screening measurement in this disease.

Cellular radiosensitivity testing

Clonogenic survival of patient fibroblasts after graded irradiation. It is not a specific test - it is abnormal across the DNA repair defects - but it is the measurement that flags the disease as a radiosensitive immunodeficiency and therefore directly changes transplant conditioning.

Show evidence (1 reference)

PMID:36341401 SUPPORT In Vitro

"Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"

Documents the clonogenic-survival assay as it was applied in a diagnosed patient.

Molecular genetic testing of LIG1

Confirmatory, and in practice the only way the diagnosis is made: every reported patient reached it through whole-exome sequencing or a primary immunodeficiency gene panel, usually after years of a CVID or SCID label. A plausible genotype must retain residual activity on at least one allele.

Show evidence (1 reference)

PMID:30395541 SUPPORT Human Clinical

"Lacking a specific genetic diagnosis, each was diagnosed with a form of common variable immune deficiency (CVID), and has been treated with replace - ment immunoglobulin."

Documents the diagnostic path that molecular testing corrects - a CVID label held until sequencing identified LIG1. The quote preserves the source PDF's "replace-|ment" line-break hyphenation.

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

Eight individuals published between 1992 and 2024. No prevalence or incidence estimate exists and none is computable from a cohort this size. The 2022 case report counted six patients in the literature; the 2018 series contributed five of those, the 1992 index case one, and the 2022 and 2024 reports added one each.

Show evidence (1 reference)

PMID:36341401 SUPPORT Human Clinical

"DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature."

Establishes the size of the published cohort as of 2022, before that report's own patient and the 2024 patient were added.

🐁

Animal Models

2

Lig1 R771W knock-in mouse

A knock-in of the recurrent human allele. Its value here is largely as a negative result: the mice are viable, and their haematopoietic lineages are preserved, so the model does not reproduce the human immunological phenotype. What it does show is early growth failure with extramedullary haematopoiesis that later resolves, and an excess of spontaneous tumours with age.

Species

Mouse

Genotype

Lig1 R771W homozygous

Publication

PMID:30395541

Pathograph links

Impaired Lymphocyte Development and Proliferation fails to recapitulate fidelity: low observes: organism Mice homozygous for the same substitution that causes human disease keep their haematopoietic lineages intact, so the central human lesion is not reproduced.

Limitations: Species divergence in DNA ligase biology is documented for this gene family: reviews of the ligase deficiency syndromes note that mouse and human cells give different results and that the relative contributions of the three ligases differ between species. The mouse therefore cannot be used to argue either for or against a mechanism for the human immune phenotype.

Show evidence (2 references)

PMID:30395541 SUPPORT Model Organism

"mice with homozygous R771W mutations were viable and had pre- served hematopoietic lineages but early growth failure"

Records the preserved haematopoietic lineages that make this a failure to recapitulate. The link's own claim is that the model fails, and this result establishes that claim, so the direction is SUPPORT; `supports` records direction, not whether the underlying result is negative. The quote preserves the source PDF's "pre-|served" line-break hyphenation.

+ 1 more reference

Lig1 null mouse

The complete-loss model, and the one that complicates the human story most usefully. Two independently targeted null alleles give the same phenotype: embryos develop normally to mid-gestation and then die of a haematopoietic defect that fetal-liver reconstitution experiments show to be a quantitative proliferative deficiency, not a block in any lineage. Null fibroblasts accumulate replication intermediates and are genomically unstable while showing no demonstrable repair deficiency, which is the source of the authors' proposal that the instability arises directly from the replication defect. Most pointedly, null cells outperform a human LIG1 point mutant in survival and replication assays, so a defective ligase can be worse than no ligase - presumably because a catalytically crippled enzyme still occupies the nick and blocks compensation by LIG3.

Species

Mouse

Genotype

Lig1 knockout (two independent targeted null alleles), homozygous

Publication

PMID:11896201

Pathograph links

Persistent Single-Strand Nicks and Replication-Associated DNA Breaks recapitulates fidelity: moderate observes: cellular Null fibroblasts show the accumulation of unfinished replication intermediates and the resulting genome instability that this node asserts.

Limitations: The genotype is a complete null, which no patient has; the human disease is always partial. The direction of the difference is not the intuitive one, because null mouse cells behave better in survival assays than a human LIG1 point mutant, so this model is not simply a more severe version of the patient state.

Show evidence (2 references)

PMID:11896201 SUPPORT In Vitro

"DNA ligase I null fibroblasts from Lig1 mutant embryos showed an accumulation of DNA replication intermediates and increased genome instability."

Demonstrates the replication-intermediate accumulation and genome instability that this pathophysiology node describes.

+ 1 more reference

Impaired Lymphocyte Development and Proliferation partially recapitulates fidelity: low observes: organism The null embryo's lethal lesion is haematopoietic and proliferative, which matches the proposed mechanism for the human lymphoid failure. It is only a partial match because the mouse defect is quantitative across the whole haematopoietic compartment with no lineage specificity, whereas the human disease is lymphoid-weighted.

Limitations: The model dies in mid-gestation, so it cannot report on lymphocyte development, antibody production or any postnatal immune phenotype. It also carries a genotype that does not occur in patients.

Show evidence (1 reference)

PMID:11896201 SUPPORT Model Organism

"we demonstrate that the haematopoietic defect in DNA-ligase-I-deficient embryos is a quantitative deficiency relating to reduced proliferation rather than a qualitative block in any haematopoietic lineage."

Establishes that the haematopoietic failure is proliferative and non-lineage-specific, which is the partial match and also the mismatch.

Show evidence (1 reference)

PMID:11896201 SUPPORT Model Organism

"Our previous finding that Lig1 knockout mouse embryos developed normally to mid-term before succumbing to a specific haematopoietic defect was difficult to reconcile with a report that DNA ligase I is essential for the viability of cultured mammalian cells."

Establishes the model's basic phenotype - mid-gestational lethality from a haematopoietic defect - which is what makes it informative about whether a human null could survive.

{ }

Source YAML

click to show

name: Immunodeficiency 96
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 96
  term:
    id: MONDO:0030693
    label: immunodeficiency 96
description: >
  Immunodeficiency 96 (IMD96; OMIM 619774), also called DNA ligase I deficiency
  or LIG1 syndrome, is an ultra-rare autosomal recessive inborn error of
  immunity caused by biallelic hypomorphic variants in LIG1. LIG1 encodes DNA
  ligase 1, the replicative ligase that seals the roughly fifty million nicks
  left between Okazaki fragments in every round of lagging-strand synthesis and
  that also completes the final ligation step of base excision, nucleotide
  excision and mismatch repair.

  The defining laboratory picture is hypogammaglobulinemia with lymphopenia, an
  increased proportion of circulating gamma-delta T cells, and erythrocyte
  macrocytosis, on a background of cellular hypersensitivity to ionizing
  radiation and alkylating agents. Clinically the disease is a spectrum rather
  than a single presentation, running from a CVID-like antibody deficiency
  managed with immunoglobulin replacement to T-B-NK+ severe combined
  immunodeficiency with Omenn-like features requiring haematopoietic stem cell
  transplantation in infancy. The spread is not explained by genotype alone:
  within one consanguineous kindred, three relatives homozygous for the same two
  variants split into two brothers transplanted for SCID and a cousin managed on
  immunoglobulin and antibiotics.

  Two things make the entry mechanistically distinctive. First, no patient has
  ever been reported with complete biallelic loss of LIG1; every published
  genotype retains at least one allele with residual catalytic activity, which
  is read in the literature as evidence that a true null is not survivable.
  Second, and unlike DNA ligase IV deficiency - whose immunodeficiency is
  cleanly explained by failed V(D)J recombination - the route from a general
  replicative ligation defect to a lineage-weighted immune failure is not
  established. That gap is curated explicitly rather than papered over with a
  plausible chain.

synonyms:
- IMD96
- DNA ligase I deficiency
- DNA ligase 1 deficiency
- LIG1 deficiency
- LIG1 syndrome
- immunodeficiency, autosomal recessive due to LIG1 deficiency

parents:
- Inborn error of immunity
- DNA repair disorder
- Chromosomal instability syndrome

mappings:
  ncit_mappings:
  - term:
      id: NCIT:C122658
      label: DNA Ligase I Deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCI Thesaurus carries the disease under its enzyme-deficiency name rather
      than under the OMIM numbering, but it denotes the same entity: inherited
      deficiency of DNA ligase I. exactMatch rather than closeMatch because
      neither term is narrower than the other - "immunodeficiency 96" and "DNA
      ligase I deficiency" are the OMIM and enzymological names for one disease.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation."
      explanation: >-
        The disease presents and is managed as an inborn error of immunity across
        its whole severity range, which is Harrison's immune/rheumatologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity."
      explanation: >-
        States the Mendelian, autosomal recessive architecture of the disease,
        placing it in Harrison's genetics Part.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS 2022 phenotypic classification, Table 2 ("Combined immunodeficiencies
      with associated or syndromic features"), subtable 2 "DNA Repair Defects
      Other Than Those Listed in Table 1", where "Ligase I deficiency" is listed
      between POLE2 deficiency and NSMCE3 deficiency. The syndromic placement is
      the committee's, and it is worth flagging that it fits the index patient
      (growth retardation, sun sensitivity) better than it fits most of the
      later ones: four of the eight published patients had entirely normal growth,
      and seven of eight had normal mentation, so the extra-immune features are
      variable rather than obligate.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells"
      explanation: >-
        The "Associated features" cell of the IUIS Ligase I deficiency row in the
        DNA-repair-defect subtable of Table 2. The presence of non-immunological
        associated features is what places the disease in the syndromic combined
        immunodeficiency table rather than in Table 1.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every reported patient carries two LIG1 variants, either compound
    heterozygous or homozygous in consanguineous kindreds; heterozygous parents
    and siblings are unaffected, although heterozygous cells show intermediate
    damage responses in vitro.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity."
    explanation: >-
      States the autosomal recessive, partial (hypomorphic) nature of the
      disease-causing genotypes.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ligase I deficiency LIG1 AR 126391 Lymphopenia,"
    explanation: >-
      The IUIS row records the gene, the autosomal recessive inheritance mode and
      the OMIM gene entry for DNA ligase I deficiency.

notes: >
  MONDO's own cross-references for MONDO:0030693 are DOID:0061066,
  MEDGEN:1810465, OMIM:619774 and UMLS:C5676930. `DiseaseMappings` has slots only
  for ICD-10-CM, ICD-11 foundation, MONDO and NCIT, so those four identifiers are
  recorded here rather than in mapping slots that do not exist. No ICD-10-CM or
  ICD-11 mapping is asserted: the closest available codes (D84.9
  "Immunodeficiency, unspecified", ICD-11 4A00.x) are broad enough to be
  uninformative, and a broadMatch to an unspecified-immunodeficiency code would
  add a mapping without adding a fact. No Orphanet code for this entity was
  found, and there is no second MONDO term to map - MONDO:0030693 is a leaf with
  one parent (MONDO:0021094 immunodeficiency disease), no descendants and a
  single causal-gene relation (RO:0004003 to hgnc:6598 LIG1), which is the leaf
  signature that makes this a DISEASE entry rather than a grouping or a subtype.

  Ultra-rare, and the cohort is small enough that every number in this entry is
  a count rather than a frequency. The index case was reported in 1992 (the
  46BR cell line, from a young woman who died at 19 of pneumonia with lymphoma);
  the disease was defined as an entity in 2018 by Maffucci et al., who described
  five patients from three kindreds; a 2022 case report added a seventh patient
  with Omenn-like SCID; and a 2024 report added an eighth with a homozygous A624T
  allele and tabulated all eight cases to that date. A 2026 single-case report
  (PMID:42527943) describes further compound heterozygous LIG1 children, but it
  is not cited anywhere in this entry: PubMed exposes no abstract or full text
  for that record, so no exact-quote snippet can be taken from it and no claim
  here rests on it. The counts above therefore describe the 1992-2024 literature
  and are a floor rather than a current total. `frequency:` is therefore left
  unset on every phenotype: with eight patients, an HPO frequency band
  would imply a precision the literature does not have.

  Two claims that a reader might expect are deliberately absent. There is no
  GeneReviews chapter for LIG1 deficiency - a PubMed search for
  `(DNA ligase I deficiency OR LIG1 deficiency OR immunodeficiency 96) AND
  GeneReviews[All Fields]` returns nothing - so the phenotype baseline here is
  the primary literature rather than an expert chapter. And no prevalence or
  incidence estimate exists; the only quantitative population statement in the
  source literature is Maffucci's carrier-frequency arithmetic, which is
  recorded under `prevalence` as an allele-frequency-derived upper bound and
  not as an observed rate.

  Lymphoma is recorded as a phenotype but with an explicit caveat: it was seen
  in one patient (the 1992 index case, whose liver showed lymphocytic
  infiltrates suggesting lymphoma) and in aged Lig1 R771W mice. One human
  case plus a mouse observation is a signal to watch, not an established
  cancer predisposition, and the entry says so rather than promoting it to a
  surveillance recommendation.

  Deep research was requested from `falcon` and fell back to `openscientist`
  after a provider billing error (HTTP 402); the committed report is
  `research/Immunodeficiency_96-deep-research-openscientist.md`. Its reference
  validation was clean (4/4 verified, no unresolved references) and its term
  validation flagged one obsolete CURIE, `GO:0006266` "DNA ligation", which is
  not used here. `just preflight-dr` returned WARN on a rival-gene signal for
  "HP"; that is a false positive - every bare "HP" in the report is the ontology
  prefix quoted inside the report's own auto-generated term-validation section,
  not haptoglobin - and the disease identity checks out otherwise (LIG1 dominant
  at 29 mentions, and the report's OMIM 619774 matches MONDO's xref). The
  report's HPO frequency table (n/N per phenotype) was read but deliberately not
  transcribed, for the reason given above. Its identifier list gives MedGen as
  C5676930, which is the UMLS CUI; MONDO's actual MedGen xref is 1810465, and
  the corrected values are the ones recorded above.

  `conforms_to` was considered and not declared. The three candidate modules -
  `genome_instability_mutation`, `genomic_instability_aging` and
  `dna_repair_synthetic_lethality` - are all framed for a different output:
  the first two for tumour evolution and for age-dependent damage
  accumulation respectively, and the third for therapeutic vulnerability of
  HRR-deficient tumours. IMD96 is a constitutional replicative-ligation defect
  whose output is a developmental haematopoietic and lymphoid failure, and the
  mutator/clonal-evolution nodes those modules require are not what this
  disease is about. A module for constitutional replication-stress
  immunodeficiency would take this entry, IMD55 (GINS1) and IMD80 (MCM10) as
  its first conformers.

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Eight individuals published between 1992 and 2024. No prevalence or incidence
    estimate exists and none is computable from a cohort this size. The 2022
    case report counted six patients in the literature; the 2018 series
    contributed five of those, the 1992 index case one, and the 2022 and 2024
    reports added one each.
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature."
    explanation: >-
      Establishes the size of the published cohort as of 2022, before that
      report's own patient and the 2024 patient were added.

pathophysiology:
- name: Biallelic Hypomorphic LIG1 Variants
  biological_scale: MOLECULAR
  description: >-
    Two LIG1 alleles of reduced function. The allelic spectrum runs from
    frameshift alleles that delete the entire catalytic core (T415Mfs*10,
    P260*) through active-site and DNA-binding missense alleles of graded
    severity (E566K, R771W, R641L, A624T). Crucially the two alleles are never
    both null: every reported genotype retains residual catalytic activity,
    which the field reads as evidence that complete LIG1 loss is not compatible
    with life.
  genes:
  - preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
    modifier: DECREASED
  genetic_context:
    description: >-
      Biallelic germline LIG1 alleles, compound heterozygous in the
      non-consanguineous kindreds and homozygous in the consanguineous ones.
      Recorded as PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION because
      the disease state is necessarily a partial one - a genotype with no
      residual ligase activity has never been observed in a patient.
    allelic_events:
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - SPLICE_SITE_VARIANT
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: DNA ligase (ATP) activity
    modifier: DECREASED
    term:
      id: GO:0003910
      label: DNA ligase (ATP) activity
  downstream:
  - target: Impaired Okazaki Fragment Ligation
    causal_link_type: DIRECT
    description: >-
      Reduced ligase activity leaves lagging-strand nicks unsealed. The 46BR
      fibroblast strain from the index patient demonstrated this directly:
      retarded joining of Okazaki fragments alongside the ligase defect.
    evidence:
    - reference: PMID:1581963
      reference_title: "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The data indicate that human DNA ligase I is required for joining of Okazaki fragments during lagging-strand DNA synthesis and the completion of DNA excision repair."
      explanation: >-
        Establishes the causal step from a LIG1 catalytic defect to failed
        Okazaki-fragment joining, which is the edge asserted here.
  - target: Abortive Ligation and Accumulation of Adenylated DNA
    causal_link_type: DIRECT
    description: >-
      Two of the patient alleles do not simply ligate more slowly - they
      transfer AMP to the nick and then release the intermediate before sealing
      it, which is a distinct biochemical lesion from reduced turnover.
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA."
      explanation: >-
        Directly links the mutant alleles to premature release of the adenylated
        intermediate, which is the abortive-ligation node.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1."
    explanation: >-
      Establishes the biallelic LIG1 genotype as the initiating lesion in the
      disease-defining series.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, all reported LIG1 patients have at least one hypomorphic allele that preserves some residual function, suggesting that full loss of function may be incompatible with life."
    explanation: >-
      Supports recording the impact as partial rather than complete loss of
      function: no observed genotype is a double null.

- name: Impaired Okazaki Fragment Ligation
  biological_scale: MOLECULAR
  description: >-
    LIG1 seals the nick between adjacent Okazaki fragments on the lagging
    strand, a step repeated tens of millions of times per replication cycle.
    With reduced ligase activity these nicks persist, so the lagging strand
    leaves S phase discontinuous.
  biological_processes:
  - preferred_term: Okazaki fragment processing
    modifier: DECREASED
    term:
      id: GO:0033567
      label: DNA replication, Okazaki fragment processing
  downstream:
  - target: Persistent Single-Strand Nicks and Replication-Associated DNA Breaks
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:1581963
    reference_title: "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These cells exhibit retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents."
    explanation: >-
      Demonstrates retarded Okazaki-fragment joining in patient-derived
      fibroblasts carrying the LIG1 mutations.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LIG1 is the most critical ligase for DNA replication, connecting over 50 million Okazaki fragments during every replication cycle"
    explanation: >-
      Quantifies the scale of the ligation burden that this node describes, which
      is why a partial activity loss is not buffered.

- name: Abortive Ligation and Accumulation of Adenylated DNA
  biological_scale: MOLECULAR
  description: >-
    A lesion specific to certain LIG1 alleles, and not the same thing as being
    slow. R641L and R771W bind Mg2+ poorly, catalyse adenylyl transfer to the
    nick, then dissociate before sealing it. Because LIG1 is immediately
    re-adenylylated it cannot rebind the intermediate, so the abortive product
    is a 5'-adenylated nick that only aprataxin or flap-displacement synthesis
    can clear. It therefore blocks the very lesion it was meant to repair.
  molecular_functions:
  - preferred_term: DNA ligase (ATP) activity, aborting after adenylyl transfer
    modifier: ABNORMAL
    term:
      id: GO:0003910
      label: DNA ligase (ATP) activity
  downstream:
  - target: Persistent Single-Strand Nicks and Replication-Associated DNA Breaks
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Under these conditions, R641L and R771W underwent abortive ligation approximately 50% of the time, compared with less than 1% for WT and the P529L variant"
    explanation: >-
      Quantifies abortive ligation for the two patient alleles at physiological
      ATP and Mg2+ against wild-type and against the neutral P529L allele.
  - reference: PMID:39510190
    reference_title: "Rare variants of DNA ligase 1 show distinct mechanisms of deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency."
    explanation: >-
      Confirms abortive ligation as a distinct biochemical defect of the patient
      alleles, and records that its individual sufficiency for disease is open.

- name: Persistent Single-Strand Nicks and Replication-Associated DNA Breaks
  biological_scale: CELLULAR
  description: >-
    Unsealed nicks from replication and from unfinished excision repair persist
    into and beyond S phase. Encountered by a replication fork, a single-strand
    nick is converted into a one-ended double-strand break, which is why cells
    with a purely ligation-level defect show gamma-H2AX foci - a
    double-strand-break marker - both at baseline and after irradiation.
  biological_processes:
  - preferred_term: single strand break repair
    modifier: DECREASED
    term:
      id: GO:0000012
      label: single strand break repair
  - preferred_term: base-excision repair
    modifier: DECREASED
    term:
      id: GO:0006284
      label: base-excision repair
  downstream:
  - target: Genomic Instability and Hypersensitivity to DNA-Damaging Agents
    causal_link_type: DIRECT
    description: >-
      The unusual feature of this step is that the instability is attributed to
      the replication defect itself rather than to a co-existing repair failure.
      Lig1-null mouse cells have no demonstrable repair deficiency and are still
      genomically unstable, which is what the source's "unusually" is doing.
    evidence:
    - reference: PMID:11896201
      reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the absence of a demonstrable deficiency in DNA repair we postulate that, unusually, genome instability may result directly from the DNA replication defect."
      explanation: >-
        Asserts the causal step from the replication defect to genome instability,
        which is this edge rather than either node alone.
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."
    explanation: >-
      Shows that patient cells carry an elevated baseline burden of DNA damage,
      not merely an impaired response to an applied insult.
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As result, Okazaki fragments are improperly catalyzed during cell replication and single-strand DNA damage repair."
    explanation: >-
      States the dual replicative and single-strand-repair consequence that this
      node represents.

- name: Genomic Instability and Hypersensitivity to DNA-Damaging Agents
  biological_scale: CELLULAR
  description: >-
    The cellular signature of the disease: patient fibroblasts and
    EBV-transformed B cells lose viability after alkylating agents and after
    ionizing radiation, and patient T cells accumulate excess gamma-H2AX after
    irradiation. Heterozygous relatives show an intermediate response, which is
    a dose effect rather than a threshold one.
  biological_processes:
  - preferred_term: cellular response to DNA damage stimulus
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Impaired Lymphocyte Development and Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded as having unknown intermediates on purpose. That LIG1-deficient
      lymphocytes handle DNA damage badly is established; the steps from that to
      a lineage-weighted developmental failure are not, and a review of the
      ligase deficiency syndromes states outright that the cause of the
      immunodeficiency in DNA ligase I deficiency is unknown.
    evidence:
    - reference: PMID:31630206
      reference_title: "Altered DNA ligase activity in human disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known."
      explanation: >-
        Supports drawing this edge as indirect with unknown intermediates rather
        than as a mechanistic chain, by stating that the mechanism is unknown.
  - target: Impaired Erythroid DNA Synthesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Somatic Hypermutation Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data indicate that both B and T cells demonstrate a decreased capacity to respond to chemical and radiation-induced DNA damage."
    explanation: >-
      Establishes the damage-response defect in the two lymphocyte lineages that
      carry the clinical phenotype.
  - reference: PMID:1581963
    reference_title: "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These cells exhibit retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents."
    explanation: >-
      The original demonstration of broad DNA-damage hypersensitivity in
      LIG1-mutant patient cells.

- name: Impaired Lymphocyte Development and Proliferation
  biological_scale: CELLULAR
  description: >-
    The lymphoid compartment is hit hardest, which is the observation the
    literature explains by lymphocyte precursors being among the most rapidly
    dividing cells in the body and therefore the most exposed to a replicative
    ligation defect. Patients show reduced T and B cell counts, depressed
    proliferation to mitogen, and a relative expansion of gamma-delta T cells.
  biological_processes:
  - preferred_term: lymphocyte proliferation
    modifier: DECREASED
    term:
      id: GO:0046651
      label: lymphocyte proliferation
  - preferred_term: B cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030183
      label: B cell differentiation
  - preferred_term: T cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030217
      label: T cell differentiation
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients P1 and P2 presented with hypogammaglobulinemia presumably through impaired B lymphocyte development."
      explanation: >-
        Asserts the step from impaired B lymphocyte development to the antibody
        deficit. The source's "presumably" is why the edge is worth citing
        explicitly rather than treating as established.
  - target: Decreased total lymphocyte count
    causal_link_type: DIRECT
  - target: Increased gamma-delta T cell proportion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The gamma-delta expansion is proportional rather than absolute and its
      mechanism is a hypothesis in the source, not a demonstrated step: either
      failed commitment of precursors to the alpha-beta lineage or inefficient
      recombination at the alpha-beta locus.
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a defect in DNA replication and repair caused by LIG1 mutations may lead to ineffective commitment of T cell precursors to the αβ lineage or inefficient recombination of the αβ locus"
      explanation: >-
        The source offers this as a candidate explanation ("may lead to"), which
        is why the edge is drawn with unknown intermediates.
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"
    explanation: >-
      States both the lymphoid phenotype and the proliferative-exposure argument
      that this node rests on.
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"
    explanation: >-
      Reports the T-lymphopenia-with-gamma-delta-expansion pattern in every
      patient of the defining series.

- name: Somatic Hypermutation Defect
  biological_scale: CELLULAR
  description: >-
    A B-cell-intrinsic finding separate from the numerical B cell defect.
    Sequencing of VH3 clones from one patient showed both fewer mutated clones
    and a smaller extent of mutation per clone than in parents, siblings or
    controls - a role for LIG1 in somatic hypermutation that was not previously
    recognised. This is a single-patient result and is curated as such.
  biological_processes:
  - preferred_term: somatic hypermutation of immunoglobulin genes
    modifier: DECREASED
    term:
      id: GO:0016446
      label: somatic hypermutation of immunoglobulin genes
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation extent was significantly reduced in P1, suggest - ing that LIG1 has a greater role during somatic hypermutation than previously known."
    explanation: >-
      Reports the reduced extent of somatic hypermutation in the patient studied
      and the authors' inference about LIG1's role. The quote preserves the
      source PDF's "suggest-|ing" line-break hyphenation.

- name: Impaired Erythroid DNA Synthesis
  biological_scale: CELLULAR
  description: >-
    Erythroid precursors cannot replicate DNA fast enough relative to cytoplasmic
    maturation, giving the megaloblastic-type dissociation that produces large
    red cells. The mechanism is proposed rather than demonstrated: the 2018
    series says the exact mechanism is not clear and offers slowed DNA synthesis
    as the explanation, which is the standard route to macrocytosis.
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  downstream:
  - target: Increased mean corpuscular volume
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LIG1 deficiency may lead to increased erythro - cyte size through failure to produce DNA quickly enough during replication."
      explanation: >-
        States the step from slowed replicative DNA synthesis to increased
        erythrocyte size, which is exactly this edge. The quote preserves the
        source PDF's "erythro-|cyte" line-break hyphenation.
  - target: Macrocytic anemia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LIG1 deficiency may lead to increased erythro - cyte size through failure to produce DNA quickly enough during replication."
    explanation: >-
      The proposed mechanism for the macrocytosis, stated by the source as a
      possibility. The quote preserves the source PDF's "erythro-|cyte"
      line-break hyphenation.
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Macrocytic anemia probably results from an impaired DNA synthesis in hematopoietic precursor cells"
    explanation: >-
      An independent statement of the same proposed mechanism, and the reason
      this node is separated from the lymphoid arm.

phenotypes:
- category: Immune
  name: Hypogammaglobulinemia
  description: >-
    The most consistent immunological finding, present in every reported
    patient and the reason most of them were on immunoglobulin replacement
    before a molecular diagnosis existed. Severity ranges from an isolated IgG
    deficit to pan-hypogammaglobulinemia.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  sequelae:
  - target: Recurrent infections
    description: >-
      Failure of humoral immunity is the proximate cause of the recurrent
      sinopulmonary and viral infections that bring these patients to attention.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."
    explanation: >-
      Reports hypogammaglobulinemia as one of the four defining laboratory
      features of the series.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."
    explanation: >-
      Independent confirmation in a patient with a different genotype, and the
      severe (pan-hypogammaglobulinemic) end of the range.

- category: Immune
  name: Decreased total lymphocyte count
  description: >-
    Lymphopenia affecting both T and B compartments, ranging from modest
    reductions in the antibody-deficient patients to the profound pattern that
    led to a SCID diagnosis in four of them, three with NK cells preserved
    (T-B-NK+).
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  sequelae:
  - target: Recurrent infections
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."
    explanation: >-
      Reports lymphopenia among the defining laboratory features.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ligase I deficiency LIG1 AR 126391 Lymphopenia,"
    explanation: >-
      The IUIS row records lymphopenia as the T-cell column entry for DNA ligase
      I deficiency.

- category: Immune
  name: Decreased total T cell count
  description: >-
    Reduced absolute CD3+, CD4+ and CD8+ counts. This is the axis that separates
    the antibody-deficient end of the spectrum from the SCID end; in the two
    Sudanese brothers and the Saudi patient the T cell counts were low enough
    to prompt transplantation.
  phenotype_term:
    preferred_term: T lymphocytopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"
    explanation: >-
      Reports T cell lymphopenia in all patients of the defining series.

- category: Immune
  name: Decreased total B cell count
  description: >-
    Low circulating CD19+ B cells in most patients, and persistent B
    lymphopenia after transplantation in at least two, where myeloid or B-cell
    engraftment was incomplete.
  phenotype_term:
    preferred_term: B lymphocytopenia
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"
    explanation: >-
      Records decreased B cell counts as part of the established clinical
      picture of LIG1 deficiency.

- category: Immune
  name: Increased gamma-delta T cell proportion
  description: >-
    A relative expansion of gamma-delta T cells within the CD3+ pool, reported
    in every patient in whom it was measured and reaching 93% in one. It is a
    useful diagnostic pointer because it is shared with other DNA repair defects
    (ataxia-telangiectasia, hypomorphic RAG1) but is not a feature of LIG4
    deficiency.
  phenotype_term:
    preferred_term: Increased gamma-delta T cell proportion
    term:
      id: HP:0500270
      label: Increased gamma-delta T cell proportion
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."
    explanation: >-
      Reports the increased gamma-delta T cell proportion as a defining feature.
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy."
    explanation: >-
      Independent statement that the gamma-delta expansion is among the most
      common manifestations of the disease.

- category: Immune
  name: Decreased mitogen-induced T-cell proliferation
  description: >-
    Depressed in vitro lymphocyte responses to phytohaemagglutinin, reported at
    6% of the control response in the 2024 patient. Mechanistically this is the
    functional read-out closest to the underlying lesion: a cell that cannot
    complete lagging-strand ligation cannot sustain a proliferative burst.
  phenotype_term:
    preferred_term: Decreased mitogen-induced T-cell proliferation
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."
    explanation: >-
      Reports the diminished mitogen response directly.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ligase I deficiency LIG1 AR 126391 Lymphopenia,"
    explanation: >-
      The IUIS T-cell column for Ligase I deficiency reads "Lymphopenia,
      increased gamma-delta T cells, decreased mitogen response"; this quote is
      the resolvable leading substring of that cell.

- category: Immune
  name: Recurrent infections
  description: >-
    Recurrent bacterial and viral infections, weighted toward the respiratory
    tract. The reported organisms are those expected of combined humoral and
    cellular failure - adenovirus, rhinovirus, metapneumovirus, RSV, rotavirus,
    Candida - and one patient developed localized BCGitis after vaccination.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells"
    explanation: >-
      The IUIS associated-features cell lists recurrent bacterial and viral
      infections first among the clinical manifestations.

- category: Blood
  name: Macrocytic anemia
  description: >-
    Anemia with a raised MCV, present in all eight reported patients and severe
    enough to require repeated transfusion in three. It is the feature most
    likely to be misread: two patients were investigated for transcobalamin II
    deficiency before a genetic diagnosis, and B12 and folate were normal with
    no response to supplementation.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy."
    explanation: >-
      Lists macrocytic anemia among the most common manifestations of the
      disease.

- category: Blood
  name: Increased mean corpuscular volume
  description: >-
    Erythrocyte macrocytosis is present even where anemia is mild, and the 2018
    series calls it the one feature shared by every patient including the 1992
    index case. Reported MCVs ranged from 95.6 to 133 fL.
  phenotype_term:
    preferred_term: Erythrocyte macrocytosis
    term:
      id: HP:0005518
      label: Increased mean corpuscular volume
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"
    explanation: >-
      States that red cell macrocytosis is shared by every reported patient,
      which is why it is curated separately from the anemia.

- category: Blood
  name: Decreased total neutrophil count
  description: >-
    Neutropenia was reported in the 2024 patient, in whom it accompanied a
    perianal abscess and localized BCGitis. It is not a feature of the 2018
    series, so this is a genotype- or patient-specific finding rather than a
    core feature.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."
    explanation: >-
      Reports neutropenia in the patient with the homozygous A624T genotype.

- category: Genitourinary
  name: Multicystic kidney dysplasia
  description: >-
    Present in the two Sudanese brothers of the 2018 series, one with an ectopic
    kidney. This is the clearest structural developmental anomaly in the disease
    and is worth recording because it does not follow from immune failure: it
    implies that the replicative defect has consequences during organogenesis,
    in a tissue with no immunological role.
  phenotype_term:
    preferred_term: Multicystic dysplastic kidney
    term:
      id: HP:0000003
      label: Multicystic kidney dysplasia
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both were diagnosed as infants with SCID, complicated by multicystic dysplastic kidneys and severe anemia requiring blood transfusions."
    explanation: >-
      Reports multicystic dysplastic kidneys in the two brothers at the severe end
      of the defining series.

- category: Integument
  name: Eczematoid dermatitis
  description: >-
    Severe eczema in one patient of the 2018 series, and an
    erythematous-exfoliative rash in the 2022 infant that prompted a working
    diagnosis of Omenn syndrome and responded to prednisone and ciclosporin.
    Whether these are the same phenomenon is not established.
  phenotype_term:
    preferred_term: Severe eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe eczema; severe anemia; no dysmorphia"
    explanation: >-
      The complications cell of the clinical table for the patient in whom severe
      eczema was recorded.

- category: Eye
  name: Conjunctival telangiectasia
  description: >-
    Ocular telangiectasia in the 1992 index patient. Its significance is
    diagnostic rather than mechanistic: combined with the immunodeficiency and
    radiosensitivity it makes ataxia-telangiectasia the first differential, and
    the absence of intellectual disability and of ataxia is what distinguishes
    them.
  phenotype_term:
    preferred_term: Ocular telangiectasia
    term:
      id: HP:0000524
      label: Conjunctival telangiectasia
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatosplenomegaly; bronchiectasis; ocular telangiectasia; sun sensitivity;"
    explanation: >-
      The complications cell of the clinical table for the index patient, listing
      ocular telangiectasia.

- category: Respiratory
  name: Bronchiectasis
  description: >-
    Recorded in the 1992 index patient, who died of pneumonia at 19. It is best
    read as the structural end-organ cost of two decades of untreated antibody
    deficiency rather than as a primary feature, which is the argument for early
    immunoglobulin replacement.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatosplenomegaly; bronchiectasis; ocular telangiectasia; sun sensitivity;"
    explanation: >-
      The complications cell of the clinical table for the index patient, listing
      bronchiectasis.

- category: Cellular
  name: Increased sensitivity to ionizing radiation
  description: >-
    Patient-derived fibroblasts show reduced clonogenic survival after
    irradiation, at a level intermediate between healthy controls and
    Artemis-deficient radiosensitive SCID. Recorded as `Cellular` because it is
    a property of cultured patient cells, and it carries direct clinical weight:
    it constrains transplant conditioning intensity.
  phenotype_term:
    preferred_term: Cellular radiosensitivity
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"
    explanation: >-
      Reports the clonogenic-survival result in patient fibroblasts and its
      intermediate position relative to an Artemis-deficient comparator.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."
    explanation: >-
      Independent demonstration of DNA-damage hypersensitivity in patient
      fibroblasts with a different genotype.

- category: Integument
  name: Cutaneous photosensitivity
  description: >-
    Sun sensitivity was a feature of the 1992 index patient and is listed by
    IUIS among the associated features, but it was not reported in the five
    patients of the 2018 series. It is therefore variable, and its presence
    historically pointed clinicians toward Bloom syndrome rather than toward
    LIG1.
  phenotype_term:
    preferred_term: Sun sensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:1351188
    reference_title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."
    explanation: >-
      Records sun sensitivity in the index patient in whom LIG1 mutations were
      first identified.

- category: Growth
  name: Growth delay
  description: >-
    Growth retardation was prominent in the 1992 index patient (bone age 12 at
    chronological age 17, absent sexual development) and mild in two later
    patients, but four of the 2018 patients had normal growth. Curated as a
    variable feature, not an obligate one.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:1351188
    reference_title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."
    explanation: >-
      Records growth retardation in the index patient.
  - reference: PMID:35748970
    reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells"
    explanation: >-
      Growth retardation is listed among the IUIS associated features for Ligase
      I deficiency.

- category: Neoplasm
  name: Lymphoma
  description: >-
    Reported once, in the 1992 index patient, whose liver showed lymphocytic
    portal infiltrates suggestive of lymphoma and who died at 19 of pneumonia.
    A single human case is not an established cancer predisposition, and this
    entry does not treat it as one; the supporting observation in aged
    Lig1 R771W mice is recorded under `animal_models` rather than being merged
    into the human claim.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:1351188
    reference_title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."
    explanation: >-
      The single reported human lymphoma in this disease, in the index patient.

biochemical:
- name: Serum immunoglobulins
  notes: >-
    Quantitative IgG, IgA and IgM. The pattern that brings patients to
    attention is a low IgG with low or absent IgA and IgM; in the milder
    patients IgM may be preserved. Because these values are what
    immunoglobulin replacement is titrated against, a post-treatment level is
    not interpretable as a disease measurement.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis."
    explanation: >-
      Establishes hypogammaglobulinemia as a measured feature of the cohort.

- name: Mean corpuscular volume
  notes: >-
    Raised in every reported patient, from 95.6 to 133 fL. Its diagnostic value
    is that it is abnormal even in the patients whose immune phenotype is mild,
    so an unexplained macrocytosis alongside hypogammaglobulinemia is the
    combination that should prompt LIG1 sequencing. Normal vitamin B12 and
    folate, and failure to respond to supplementation, distinguish it from
    nutritional megaloblastic anemia.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"
    explanation: >-
      Supports treating raised MCV as the near-universal biochemical marker of
      the disease.

genetic:
- name: LIG1
  gene_term:
    preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    LIG1 is on chromosome 19q13.33 and encodes DNA ligase 1, the replicative
    ligase. The disease-relevant quantity is residual catalytic activity, and
    the measured values span a wide range: R771W retains about 4.5% of
    wild-type activity and R641L about 7%, while T415Mfs*10 deletes the
    catalytic core outright. P529L, present homozygously alongside R771W in
    kindred C, is a benign passenger - it has normal catalytic activity and
    normal efficiency - so the disease in that kindred is attributable to
    R771W. Recording that distinction matters: a naive reading of the kindred C
    genotype would credit two variants where only one is doing the work.
    Heterozygous carriers are healthy, and individuals with a single functional
    LIG1 allele develop normally.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1."
    explanation: >-
      Establishes LIG1 as the causal gene in the disease-defining series.
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The R771W missense mutation exhibits only 4.5% of WT activity"
    explanation: >-
      Quantifies the residual activity of the most frequently reported patient
      allele, which is the basis for calling the genotypes hypomorphic.
  - reference: PMID:39510190
    reference_title: "Rare variants of DNA ligase 1 show distinct mechanisms of deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hypomorphic LIG1 variants R771W and R641L cause immune deficiencies in LIG1 Syndrome patients."
    explanation: >-
      Independent confirmation of the gene-disease relationship and of the
      hypomorphic allele architecture.

variants:
- name: LIG1 p.Arg771Trp (R771W)
  description: >-
    The recurrent allele of this disease: present in the 1992 index patient
    (heterozygous), homozygous in all three members of kindred C, and hit at the
    same codon by a different substitution (R771G) in the 2022 Omenn-like
    patient. R771 sits next to a DNA-binding motif in the OB-fold domain, and
    the substitution both lowers catalytic activity to about 4.5% of wild type
    and weakens Mg2+ affinity, causing abortive ligation about half the time at
    physiological Mg2+. CADD 34; ExAC minor allele frequency 0.00005.
  gene:
    preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
  type: SNV
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The R771W missense mutation exhibits only 4.5% of WT activity"
    explanation: >-
      Quantifies the residual catalytic activity of this allele.
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Under these conditions, R641L and R771W underwent abortive ligation approximately 50% of the time, compared with less than 1% for WT and the P529L variant"
    explanation: >-
      Documents the abortive-ligation defect of this allele at physiological ATP
      and Mg2+ concentrations.

- name: LIG1 p.Arg641Leu (R641L)
  description: >-
    Carried in compound heterozygosity with T415Mfs*10 by two unrelated White
    patients from different countries who nonetheless shared both alleles;
    haplotype analysis found no founder effect, so the pair arose independently.
    R641 lies in a hairpin loop that contacts the minor groove of nicked DNA and
    forms a salt bridge with D600; replacing it with leucine leaves about 7% of
    wild-type activity and, like R771W, produces abortive ligation at
    physiological Mg2+. These two patients occupy the mild end of the clinical
    spectrum.
  gene:
    preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
  type: SNV
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "whereas the R641L substitution demonstrates an estimated 7% of WT activity"
    explanation: >-
      Quantifies the residual catalytic activity of this allele.

- name: LIG1 p.Thr415MetfsTer10 (T415Mfs*10)
  description: >-
    A frameshift introducing a premature stop and removing the entire catalytic
    core, expressed only at very low levels as a truncated protein. It is the
    closest thing to a null allele in the reported spectrum, and it is never
    seen with a second severe allele - both carriers pair it with R641L.
  gene:
    preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
  type: INDEL
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA."
    explanation: >-
      Supports classifying the patient allele set as containing amorphic as well
      as hypomorphic members; T415Mfs*10 is the amorphic one.

- name: LIG1 p.Ala624Thr (A624T)
  description: >-
    Homozygous in a consanguineous Saudi patient with SCID. Its interest is
    mechanistic rather than clinical: it lowers Mg2+ affinity 2.5-fold and, by
    an allosteric effect on the high-fidelity Mg2+ site, raises ligation fidelity
    more than 50-fold against 3'-8-oxoguanine mismatches. Higher fidelity is not
    a benefit here - it means the enzyme refuses to process the nicks it
    encounters, converting them into persistent single- and double-strand
    breaks. This is the one allele where a gain in one enzymatic property is
    part of the disease mechanism.
  gene:
    preferred_term: LIG1
    term:
      id: hgnc:6598
      label: LIG1
  type: SNV
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation."
    explanation: >-
      Establishes the genotype and the clinical phenotype it produced.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold."
    explanation: >-
      Quantifies the magnesium-affinity defect that underlies the reduced
      activity of this allele.

environmental:
- name: Exposure to ionizing radiation
  description: >-
    Not a cause of the disease, which is entirely germline, but a modifier of its
    cellular pathology with direct clinical consequences. Patient fibroblasts and
    lymphoblastoid lines lose viability after irradiation and accumulate excess
    gamma-H2AX foci. In practice this constrains transplant conditioning
    intensity - reduced-intensity and unconditioned regimens have been used - and
    argues for caution with diagnostic and therapeutic radiation.
  exposure_term:
    preferred_term: exposure to ionizing radiation
    term:
      id: ECTO:7000047
      label: exposure to ionizing radiation
  influences_mechanisms:
  - target: Genomic Instability and Hypersensitivity to DNA-Damaging Agents
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Irradiation adds strand breaks to a cell that already cannot seal the ones
      it generates itself, so the damage burden this node describes rises.
    evidence:
    - reference: PMID:38896336
      reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents."
      explanation: >-
        Demonstrates that an applied genotoxic insult worsens an already elevated
        baseline damage burden in patient cells.
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"
    explanation: >-
      Records the measured radiosensitivity of patient-derived cells that this
      exposure entry is about.

- name: Exposure to ultraviolet radiation
  description: >-
    Sunlight exposure in a cell that cannot complete nucleotide excision repair.
    This is the exposure behind the sun sensitivity of the index patient, and it
    supports sun protection as management, though the phenotype is variable and
    was not reported in the 2018 series.
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Genomic Instability and Hypersensitivity to DNA-Damaging Agents
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      UV lesions are repaired by excision pathways whose final step LIG1
      performs, so an unrepaired UV burden adds to the same pool of unsealed
      nicks.
    evidence:
    - reference: PMID:1581963
      reference_title: "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The data indicate that human DNA ligase I is required for joining of Okazaki fragments during lagging-strand DNA synthesis and the completion of DNA excision repair."
      explanation: >-
        Establishes LIG1's requirement for completing excision repair, which is
        the pathway that clears UV photoproducts and the basis for this edge.
  evidence:
  - reference: PMID:1351188
    reference_title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."
    explanation: >-
      Records the clinical sun sensitivity that identifies UV as a relevant
      exposure in this disease.

animal_models:
- name: Lig1 R771W knock-in mouse
  species: Mouse
  genotype: Lig1 R771W homozygous
  publication: PMID:30395541
  description: >-
    A knock-in of the recurrent human allele. Its value here is largely as a
    negative result: the mice are viable, and their haematopoietic lineages are
    preserved, so the model does not reproduce the human immunological
    phenotype. What it does show is early growth failure with extramedullary
    haematopoiesis that later resolves, and an excess of spontaneous tumours
    with age.
  modeled_mechanisms:
  - target: Impaired Lymphocyte Development and Proliferation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Mice homozygous for the same substitution that causes human disease keep
      their haematopoietic lineages intact, so the central human lesion is not
      reproduced.
    limitations: >-
      Species divergence in DNA ligase biology is documented for this gene
      family: reviews of the ligase deficiency syndromes note that mouse and
      human cells give different results and that the relative contributions of
      the three ligases differ between species. The mouse therefore cannot be
      used to argue either for or against a mechanism for the human immune
      phenotype.
    evidence:
    - reference: PMID:30395541
      reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mice with homozygous R771W mutations were viable and had pre- served hematopoietic lineages but early growth failure"
      explanation: >-
        Records the preserved haematopoietic lineages that make this a failure to
        recapitulate. The link's own claim is that the model fails, and this
        result establishes that claim, so the direction is SUPPORT; `supports`
        records direction, not whether the underlying result is negative. The
        quote preserves the source PDF's "pre-|served" line-break hyphenation.
    - reference: PMID:31630206
      reference_title: "Altered DNA ligase activity in human disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Inherited mutations in the human LIG1 and LIG4 genes that result in the generation of polypeptides with partial activity have been identified as the causative factors in rare DNA ligase deficiency syndromes that share a common clinical symptom, immunodeficiency."
      explanation: >-
        Supports the framing of the limitation: the human disease is defined by
        immunodeficiency, which is exactly what the mouse does not show.

- name: Lig1 null mouse
  species: Mouse
  genotype: Lig1 knockout (two independent targeted null alleles), homozygous
  publication: PMID:11896201
  description: >-
    The complete-loss model, and the one that complicates the human story most
    usefully. Two independently targeted null alleles give the same phenotype:
    embryos develop normally to mid-gestation and then die of a haematopoietic
    defect that fetal-liver reconstitution experiments show to be a quantitative
    proliferative deficiency, not a block in any lineage. Null fibroblasts
    accumulate replication intermediates and are genomically unstable while
    showing no demonstrable repair deficiency, which is the source of the
    authors' proposal that the instability arises directly from the replication
    defect. Most pointedly, null cells outperform a human LIG1 point mutant in
    survival and replication assays, so a defective ligase can be worse than no
    ligase - presumably because a catalytically crippled enzyme still occupies
    the nick and blocks compensation by LIG3.
  modeled_mechanisms:
  - target: Persistent Single-Strand Nicks and Replication-Associated DNA Breaks
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Null fibroblasts show the accumulation of unfinished replication
      intermediates and the resulting genome instability that this node asserts.
    limitations: >-
      The genotype is a complete null, which no patient has; the human disease is
      always partial. The direction of the difference is not the intuitive one,
      because null mouse cells behave better in survival assays than a human LIG1
      point mutant, so this model is not simply a more severe version of the
      patient state.
    evidence:
    - reference: PMID:11896201
      reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DNA ligase I null fibroblasts from Lig1 mutant embryos showed an accumulation of DNA replication intermediates and increased genome instability."
      explanation: >-
        Demonstrates the replication-intermediate accumulation and genome
        instability that this pathophysiology node describes.
    - reference: PMID:11896201
      reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the absence of a demonstrable deficiency in DNA repair we postulate that, unusually, genome instability may result directly from the DNA replication defect."
      explanation: >-
        Supports attributing the instability to the replication defect rather than
        to a separate repair failure, which is how the chain is drawn here.
  - target: Impaired Lymphocyte Development and Proliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The null embryo's lethal lesion is haematopoietic and proliferative, which
      matches the proposed mechanism for the human lymphoid failure. It is only a
      partial match because the mouse defect is quantitative across the whole
      haematopoietic compartment with no lineage specificity, whereas the human
      disease is lymphoid-weighted.
    limitations: >-
      The model dies in mid-gestation, so it cannot report on lymphocyte
      development, antibody production or any postnatal immune phenotype. It also
      carries a genotype that does not occur in patients.
    evidence:
    - reference: PMID:11896201
      reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we demonstrate that the haematopoietic defect in DNA-ligase-I-deficient embryos is a quantitative deficiency relating to reduced proliferation rather than a qualitative block in any haematopoietic lineage."
      explanation: >-
        Establishes that the haematopoietic failure is proliferative and
        non-lineage-specific, which is the partial match and also the mismatch.
  evidence:
  - reference: PMID:11896201
    reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our previous finding that Lig1 knockout mouse embryos developed normally to mid-term before succumbing to a specific haematopoietic defect was difficult to reconcile with a report that DNA ligase I is essential for the viability of cultured mammalian cells."
    explanation: >-
      Establishes the model's basic phenotype - mid-gestational lethality from a
      haematopoietic defect - which is what makes it informative about whether a
      human null could survive.

diagnosis:
- name: Lymphocyte subset immunophenotyping with gamma-delta T cell fraction
  description: >-
    Flow cytometry is the entry point, and the discriminating measurement is not
    the absolute lymphocyte count but the gamma-delta fraction of CD3+ T cells.
    An elevated gamma-delta proportion in a hypogammaglobulinemic child narrows
    the differential to the DNA repair defects and hypomorphic RAG, and away
    from LIG4 deficiency, where it is not reported.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also observed T cell lymphopenia and increased numbers of γδ T cells, especially as a fraction of CD3+ T cells, in all the patients"
    explanation: >-
      Establishes the combination of T lymphopenia with a raised gamma-delta
      fraction as present in every patient, which is what makes it useful.

- name: Full blood count with red cell indices
  description: >-
    Raised MCV is the cheapest pointer to this diagnosis and is present even
    where the immune phenotype is mild. The trap it sets is a nutritional one:
    two of the reported patients were worked up for transcobalamin II deficiency
    on the strength of the macrocytosis before genetic testing.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients, including the originally reported subject (16), share a somewhat unique clinical feature: red cell macrocytosis"
    explanation: >-
      Supports red cell indices as a near-universally abnormal screening
      measurement in this disease.

- name: Cellular radiosensitivity testing
  description: >-
    Clonogenic survival of patient fibroblasts after graded irradiation. It is
    not a specific test - it is abnormal across the DNA repair defects - but it
    is the measurement that flags the disease as a radiosensitive
    immunodeficiency and therefore directly changes transplant conditioning.
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts cultured from skin biopsy showed an intermediate sensitivity to ionizing radiation"
    explanation: >-
      Documents the clonogenic-survival assay as it was applied in a diagnosed
      patient.

- name: Molecular genetic testing of LIG1
  description: >-
    Confirmatory, and in practice the only way the diagnosis is made: every
    reported patient reached it through whole-exome sequencing or a primary
    immunodeficiency gene panel, usually after years of a CVID or SCID label. A
    plausible genotype must retain residual activity on at least one allele.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lacking a specific genetic diagnosis, each was diagnosed with a form of common variable immune deficiency (CVID), and has been treated with replace - ment immunoglobulin."
    explanation: >-
      Documents the diagnostic path that molecular testing corrects - a CVID
      label held until sequencing identified LIG1. The quote preserves the source
      PDF's "replace-|ment" line-break hyphenation.

treatments:
- name: Immunoglobulin replacement therapy
  description: >-
    The mainstay for every reported patient, before and after any transplant.
    Intravenous or weekly subcutaneous. Note that it remains necessary after
    transplantation in the patients with poor B-cell engraftment, so it is not
    a bridge to transplant but a parallel therapy.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Hypogammaglobulinemia
    description: >-
      Replaces the missing antibody rather than correcting the ligase defect, so
      it addresses the humoral consequence and nothing upstream of it.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lacking a specific genetic diagnosis, each was diagnosed with a form of common variable immune deficiency (CVID), and has been treated with replace - ment immunoglobulin."
    explanation: >-
      Documents immunoglobulin replacement as the treatment given to the milder
      patients. The quote preserves the source PDF's "replace-|ment" line-break
      hyphenation.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She is maintained on weekly subcutaneous immunoglobulin therapy."
    explanation: >-
      Records continued subcutaneous immunoglobulin six years after
      transplantation, which is the basis for saying it is not merely a bridge.

- name: Haematopoietic stem cell transplantation
  description: >-
    The only treatment that addresses the haematopoietic arm of the disease, and
    it has been used in four of the eight reported patients, at ages from four
    months to three years. Outcomes are mixed in an informative way: lymphoid
    engraftment has been good, myeloid engraftment poor or absent in three of
    the four, and two patients remained transfusion-dependent afterwards. It
    does not address the non-haematopoietic consequences of a defect that is
    present in every cell. Conditioning intensity is constrained by the cellular
    radiosensitivity and alkylator hypersensitivity, and reduced-intensity
    regimens or no conditioning at all have been used.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: haematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired Lymphocyte Development and Proliferation
    description: >-
      Replaces the LIG1-deficient haematopoietic compartment with donor cells
      that carry functional ligase, so the lymphoid arm can be reconstituted.
      Non-haematopoietic tissues keep the patient genotype.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were treated with hematopoietic stem cell transplantation."
    explanation: >-
      Records transplantation in the two brothers at the severe end of the 2018
      series.
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol."
    explanation: >-
      Documents transplantation with a reduced-intensity protocol in the
      Omenn-like patient.
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient received hematopoietic stem cell transplantation (HSCT) from her HLA-matched sister without conditioning at the age of 6 months."
    explanation: >-
      Records an unconditioned matched-sibling transplant, the least intensive
      approach reported, in a patient whose cells are radiosensitive.

- name: Antimicrobial prophylaxis
  description: >-
    Antibiotic prophylaxis alongside immunoglobulin replacement in the patient
    maintained without transplantation, and anti-viral, anti-fungal and
    anti-Pneumocystis prophylaxis in the infant with SCID before transplant.
    Recorded as documented management; no reported patient series measures its
    effect separately from immunoglobulin.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antibacterial, antiviral, antifungal and anti-Pneumocystis prophylaxis
      term:
        id: NCIT:C254
        label: Anti-Infective Agent
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she is not so profoundly T cell lymph- openic and is maintained on immune globulin replacement and antibiotics"
    explanation: >-
      Documents ongoing antibiotic prophylaxis alongside immunoglobulin in the
      untransplanted member of kindred C. The quote preserves the source PDF's
      "lymph-|openic" line-break hyphenation.

- name: Red blood cell transfusion
  description: >-
    Supportive treatment for the anemia, needed repeatedly in three patients -
    approximately every two weeks in the Omenn-like infant - and still needed
    after transplantation in two. Its persistence post-transplant is why one
    family was offered a second transplant. Transfused products were irradiated
    and filtered in the reported case.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15409
      label: Packed Red Blood Cell Transfusion
  target_mechanisms:
  - target: Macrocytic anemia
    description: >-
      Replaces circulating red cells; it does nothing to the erythroid
      progenitor defect that generates them.
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both were diagnosed as infants with SCID, complicated by multicystic dysplastic kidneys and severe anemia requiring blood transfusions."
    explanation: >-
      Records transfusion dependence in the two most severely affected patients
      of the defining series.

- name: Genetic counselling
  description: >-
    Autosomal recessive with a 25% sibling recurrence risk. Relevant in
    practice because two of the three kindreds in the defining series were
    consanguineous, and because the second reported family reached diagnosis
    only after an affected cousin was recognised.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity."
    explanation: >-
      Establishes the autosomal recessive inheritance that the counselling
      addresses. Note that the same source also establishes the variability,
      which is what makes prognostic counselling hard.

mechanistic_hypotheses:
- hypothesis_group_id: proliferative_exposure_lymphoid_selectivity
  hypothesis_label: Lymphoid precursors fail because they divide fastest, not because LIG1 has an immune-specific role
  status: EMERGING
  description: >-
    The dominant explanation in the literature for why a ubiquitous replicative
    ligase defect presents as an immunodeficiency is that lymphocyte precursors
    are among the most rapidly proliferating cells in the body and therefore
    the most exposed to an unrepaired lagging-strand lesion. The competing
    possibility - that LIG1 has a specific role in an immune-restricted process
    such as somatic hypermutation or alpha-beta/gamma-delta lineage commitment -
    is raised by the same series, which found reduced somatic hypermutation and
    a gamma-delta expansion that pure proliferative exposure does not obviously
    explain. Neither has been tested against the other.
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their clinical manifestations include hypogammaglobulinemia, decreased B and T cell counts, and lymphopenia, suggesting that rapidly dividing adaptive immune cells are more sensitive to LIG1 perturbations"
    explanation: >-
      States the proliferative-exposure hypothesis in the source's own words, as
      an inference from the clinical pattern rather than as a tested result.
  - reference: PMID:30395541
    reference_title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation extent was significantly reduced in P1, suggest - ing that LIG1 has a greater role during somatic hypermutation than previously known."
    explanation: >-
      The competing possibility: a specific LIG1 role in an immune-restricted
      process. Recorded here because it is what keeps the hypothesis EMERGING
      rather than settled. The quote preserves the source PDF's "suggest-|ing"
      line-break hyphenation.

discussions:
- discussion_id: lig1_immunodeficiency_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Lymphocyte Development and Proliferation
  - pathophysiology#Genomic Instability and Hypersensitivity to DNA-Damaging Agents
  prompt: >-
    By what mechanism does a general defect in replicative DNA ligation produce
    an immunodeficiency, when the paralogous LIG4 deficiency has a clean
    explanation in failed V(D)J recombination?
  rationale: >-
    This is the central open question of the disease and the reason the edge
    from the cellular damage phenotype to the lymphoid phenotype is drawn as
    indirect with unknown intermediates. LIG1 is required in every dividing
    cell, yet the clinical picture is dominated by lymphoid failure with
    comparatively little else. The proliferative-exposure argument is plausible
    but has never been tested against the alternative that LIG1 serves an
    immune-restricted function, and a 2020 review of the ligase deficiency
    syndromes states flatly that the cause is not known.
  evidence:
  - reference: PMID:31630206
    reference_title: "Altered DNA ligase activity in human disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known."
    explanation: >-
      States the gap directly, and contrasts it with the paralogous disease where
      the mechanism is established.

- discussion_id: lig1_which_biochemical_defect_causes_disease
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Abortive Ligation and Accumulation of Adenylated DNA
  prompt: >-
    Is reduced catalytic efficiency sufficient to cause LIG1 syndrome, or is
    abortive ligation - the release of an adenylated intermediate that other
    ligases cannot then act on - the necessary defect?
  rationale: >-
    The two known pathogenic alleles, R641L and R771W, have both defects at
    once, so nothing in the patient data separates them. The question became
    answerable in 2024 when three further rare LIG1 variants were characterised:
    R305Q and R768W lower catalytic efficiency without elevated abortive
    ligation, and R641S does both more severely than R641L. If carriers of the
    abortive-ligation-sparing alleles turn out not to have immune disease, the
    abortive intermediate is the pathogenic lesion. This bears directly on
    whether aprataxin or FEN1 activity would modify severity, which the 2018
    series proposed but could not test.
  evidence:
  - reference: PMID:39510190
    reference_title: "Rare variants of DNA ligase 1 show distinct mechanisms of deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency."
    explanation: >-
      States the gap in the exact terms it is posed here, and identifies the
      variant set that could resolve it.

- discussion_id: lig1_null_lethality_untested
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic Hypomorphic LIG1 Variants
  prompt: >-
    Is complete biallelic LIG1 loss lethal in humans, or simply not yet
    ascertained?
  rationale: >-
    Every published patient retains residual activity on at least one allele,
    and the field reads that as evidence that a true null is incompatible with
    life. The inference is reasonable but the sample is eight people, and the
    counter-evidence is not trivial. Cells lacking LIG1 remain viable because the
    other ligases compensate; mice homozygous for the human R771W allele keep
    normal haematopoiesis; and Lig1-null mouse cells actually outperform a human
    LIG1 point mutant in survival and replication assays, which points the wrong
    way for a simple dose model and suggests instead that a crippled ligase
    occupying the nick is worse than none at all. Against that, the mouse null
    is embryonic-lethal in mid-gestation from a haematopoietic proliferative
    defect, which is the strongest single piece of support for human
    null-lethality. The claim as stated is an ascertainment argument, and this
    entry records it as one rather than as an established fact.
  evidence:
  - reference: PMID:38896336
    reference_title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, all reported LIG1 patients have at least one hypomorphic allele that preserves some residual function, suggesting that full loss of function may be incompatible with life."
    explanation: >-
      States the inference and, in the word "suggesting", its epistemic status.
  - reference: PMID:11896201
    reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our previous finding that Lig1 knockout mouse embryos developed normally to mid-term before succumbing to a specific haematopoietic defect was difficult to reconcile with a report that DNA ligase I is essential for the viability of cultured mammalian cells."
    explanation: >-
      Supports the lethality side of the question: a complete null is
      embryonic-lethal in mouse, from a haematopoietic defect.
  - reference: PMID:11896201
    reference_title: "DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Lig1 null mouse cells performed better in the survival and replication assays than a human LIG1 point mutant, and we suggest that the complete absence of DNA ligase I may make it easier for another ligase to compensate for DNA ligase I deficiency."
    explanation: >-
      Cuts against the assumption that a null is necessarily worse than a
      hypomorph: at the cellular level the null is the milder state, because
      absence of the protein permits compensation that a defective protein blocks.
  - reference: PMID:39510190
    reference_title: "Rare variants of DNA ligase 1 show distinct mechanisms of deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A single copy of LIG1 is sufficient for normal development, because several individuals with a single functional allele have been described"
    explanation: >-
      Establishes the dosage boundary the question sits above: one functional
      allele is demonstrably enough, so the open question is specifically about
      zero.

- discussion_id: lig1_persistent_anemia_after_transplant
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Erythroid DNA Synthesis
  - treatments#Haematopoietic stem cell transplantation
  prompt: >-
    Why does the anemia persist after haematopoietic stem cell transplantation
    in some patients despite adequate lymphoid engraftment?
  rationale: >-
    Two transplanted patients remained transfusion-dependent or anemic with
    good lymphoid but poor myeloid chimerism. If the erythroid defect is
    cell-intrinsic to haematopoietic progenitors, as the proposed mechanism for
    the macrocytosis implies, then incomplete myeloid engraftment is a
    sufficient explanation and the remedy is a conditioning regimen that clears
    more host marrow. But conditioning intensity is exactly what the cellular
    radiosensitivity constrains, so the two requirements pull against each
    other. No study has addressed this, and one family declined the second
    transplant that would have tested it.
  evidence:
  - reference: PMID:36341401
    reference_title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Macrocytic anemia probably results from an impaired DNA synthesis in hematopoietic precursor cells"
    explanation: >-
      Supports the cell-intrinsic-progenitor premise of the question; the same
      report documents the persistent transfusion dependence after transplant.

- discussion_id: lig1_cancer_risk_uncharacterised
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - phenotypes#Lymphoma
  prompt: >-
    Do individuals with LIG1 deficiency carry an increased lifetime cancer risk,
    and does it warrant surveillance?
  rationale: >-
    A genome-instability disorder with radiosensitivity would be expected to
    predispose to malignancy, and there are two supporting observations: the
    1992 index patient had lymphocytic liver infiltrates suggestive of lymphoma
    at death aged 19, and aged Lig1 R771W mice develop an excess of spontaneous
    tumours. Against that, no malignancy has been reported in any of the seven
    later patients, all of whom are alive and most of whom are under ten years
    old - so the cohort has neither the size nor the follow-up to detect a real
    risk. No surveillance recommendation exists and none is asserted here.
  evidence:
  - reference: PMID:1351188
    reference_title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele."
    explanation: >-
      The single reported human malignancy, and the reason the question is open
      rather than closed.
  - reference: PMID:30725883
    reference_title: "Chromosome Instability Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other rare syndromes include ataxia telangiectasia-like disorder; immunodeficiency, centromeric instability, and facial anomalies syndromes; Cockayne syndrome; trichothiodystrophy; xeroderma pigmentosum; DNA ligase I deficiency; PMS2 deficiency; and DNA recombinase repair defects (DNA-phosphatidylinositol 3-kinase, Artemis, DNA ligase 4, Cernunnos)."
    explanation: >-
      Places DNA ligase I deficiency in the chromosomal instability syndrome
      family, whose members are characteristically associated with malignancy
      risk. This is the class-membership argument for asking the question, not
      evidence of risk in this disease.

references:
- reference: PMID:30395541
  title: "Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies."
- reference: PMID:1351188
  title: "Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene."
- reference: PMID:1581963
  title: "Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents."
- reference: PMID:36341401
  title: "Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation."
- reference: PMID:38896336
  title: "Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity."
- reference: PMID:39510190
  title: "Rare variants of DNA ligase 1 show distinct mechanisms of deficiency."
- reference: PMID:31630206
  title: "Altered DNA ligase activity in human disease."
- reference: PMID:30725883
  title: "Chromosome Instability Syndromes."
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."

📚

References & Deep Research

References

9

PMID:30395541

Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies.

No top-level findings curated for this source.

PMID:1351188

Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene.

No top-level findings curated for this source.

PMID:1581963

Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents.

No top-level findings curated for this source.

PMID:36341401

Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation.

No top-level findings curated for this source.

PMID:38896336

Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

No top-level findings curated for this source.

PMID:39510190

Rare variants of DNA ligase 1 show distinct mechanisms of deficiency.

No top-level findings curated for this source.

PMID:31630206

Altered DNA ligase activity in human disease.

No top-level findings curated for this source.

PMID:30725883

Chromosome Instability Syndromes.

No top-level findings curated for this source.

PMID:35748970

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.

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 (2)

Record notes

MONDO's own cross-references for MONDO:0030693 are DOID:0061066, MEDGEN:1810465, OMIM:619774 and UMLS:C5676930. `DiseaseMappings` has slots only for ICD-10-CM, ICD-11 foundation, MONDO and NCIT, so those four identifiers are recorded here rather than in mapping slots that do not exist. No ICD-10-CM or ICD-11 mapping is asserted: the closest available codes (D84.9 "Immunodeficiency, unspecified", ICD-11 4A00.x) are broad enough to be uninformative, and a broadMatch to an unspecified-immunodeficiency code would add a mapping without adding a fact. No Orphanet code for this entity was found, and there is no second MONDO term to map - MONDO:0030693 is a leaf with one parent (MONDO:0021094 immunodeficiency disease), no descendants and a single causal-gene relation (RO:0004003 to hgnc:6598 LIG1), which is the leaf signature that makes this a DISEASE entry rather than a grouping or a subtype. Ultra-rare, and the cohort is small enough that every number in this entry is a count rather than a frequency. The index case was reported in 1992 (the 46BR cell line, from a young woman who died at 19 of pneumonia with lymphoma); the disease was defined as an entity in 2018 by Maffucci et al., who described five patients from three kindreds; a 2022 case report added a seventh patient with Omenn-like SCID; and a 2024 report added an eighth with a homozygous A624T allele and tabulated all eight cases to that date. A 2026 single-case report (PMID:42527943) describes further compound heterozygous LIG1 children, but it is not cited anywhere in this entry: PubMed exposes no abstract or full text for that record, so no exact-quote snippet can be taken from it and no claim here rests on it. The counts above therefore describe the 1992-2024 literature and are a floor rather than a current total. `frequency:` is therefore left unset on every phenotype: with eight patients, an HPO frequency band would imply a precision the literature does not have. Two claims that a reader might expect are deliberately absent. There is no GeneReviews chapter for LIG1 deficiency - a PubMed search for `(DNA ligase I deficiency OR LIG1 deficiency OR immunodeficiency 96) AND GeneReviews[All Fields]` returns nothing - so the phenotype baseline here is the primary literature rather than an expert chapter. And no prevalence or incidence estimate exists; the only quantitative population statement in the source literature is Maffucci's carrier-frequency arithmetic, which is recorded under `prevalence` as an allele-frequency-derived upper bound and not as an observed rate. Lymphoma is recorded as a phenotype but with an explicit caveat: it was seen in one patient (the 1992 index case, whose liver showed lymphocytic infiltrates suggesting lymphoma) and in aged Lig1 R771W mice. One human case plus a mouse observation is a signal to watch, not an established cancer predisposition, and the entry says so rather than promoting it to a surveillance recommendation. Deep research was requested from `falcon` and fell back to `openscientist` after a provider billing error (HTTP 402); the committed report is `research/Immunodeficiency_96-deep-research-openscientist.md`. Its reference validation was clean (4/4 verified, no unresolved references) and its term validation flagged one obsolete CURIE, `GO:0006266` "DNA ligation", which is not used here. `just preflight-dr` returned WARN on a rival-gene signal for "HP"; that is a false positive - every bare "HP" in the report is the ontology prefix quoted inside the report's own auto-generated term-validation section, not haptoglobin - and the disease identity checks out otherwise (LIG1 dominant at 29 mentions, and the report's OMIM 619774 matches MONDO's xref). The report's HPO frequency table (n/N per phenotype) was read but deliberately not transcribed, for the reason given above. Its identifier list gives MedGen as C5676930, which is the UMLS CUI; MONDO's actual MedGen xref is 1810465, and the corrected values are the ones recorded above. `conforms_to` was considered and not declared. The three candidate modules - `genome_instability_mutation`, `genomic_instability_aging` and `dna_repair_synthetic_lethality` - are all framed for a different output: the first two for tumour evolution and for age-dependent damage accumulation respectively, and the third for therapeutic vulnerability of HRR-deficient tumours. IMD96 is a constitutional replicative-ligation defect whose output is a developmental haematopoietic and lymphoid failure, and the mutator/clonal-evolution nodes those modules require are not what this disease is about. A module for constitutional replication-stress immunodeficiency would take this entry, IMD55 (GINS1) and IMD80 (MCM10) as its first conformers.

Create: Immunodeficiency_96 · 2026-09-07T17:30:14Z · View source

De novo creation of the IMD96 (LIG1 / DNA ligase I deficiency) entry from the stub stubs/Immunodeficiency_96.yaml, which is deleted in the same change. LUMP/SPLIT. entry_type DISEASE. MONDO:0030693 is a leaf: one parent (MONDO:0021094 immunodeficiency disease), no descendants, and one causal-gene relation (RO:0004003 -> hgnc:6598 LIG1), confirmed against the committed stub and re-read from the MONDO OBO record while checking xrefs. Not a grouping (nothing below it), not a subtype (no curated parent disease it refines), not out of scope (it carries a mechanism). DEEP RESEARCH. falcon was requested and failed twice with HTTP 402 ProviderBillingError (Edison account out of credits). The re-run used 'just dr_fallback=--fallback research-disorder falcon Immunodeficiency_96', which fell back to openscientist. The report that was actually used and is committed is research/Immunodeficiency_96-deep-research-openscientist.md (frontmatter records fell_back: true, requested_provider: falcon), with its .citations.md sidecar and an _artifacts/ directory holding the provider's HTML and PDF renderings. No falcon report exists. REPORT VALIDATION. reference_validation: 4 total references, 4 verified, 0 not found, confabulation_rate 0.0, no unresolved_references; 2 of 4 assessed as on topic. term_validation: needs_review true - 56 terms, 53 verified, 0 not found, 1 obsolete (GO:0006266 'obsolete DNA ligation'), 2 unverifiable, 7 mislabelled. Every one of the 7 mislabelled entries is a parsing artifact where the report's frequency annotation ('2/5; Maffucci 2018') was read as a second label; the ontology labels themselves matched. The obsolete GO:0006266 was independently caught by 'just validate-terms' when I had used it for the abortive-ligation node, and was replaced with GO:0003910 (DNA ligase (ATP) activity, modifier ABNORMAL). No CURIE from the report was bound without independent OAK lookup. PREFLIGHT. 'just preflight-dr research/Immunodeficiency_96-deep-research-openscientist.md MONDO:0030693' returned WARN: rival gene 'HP' at 17 mentions (59% of LIG1's 29). Resolved as a false positive - every bare 'HP' in the report is the ontology prefix quoted inside the report's own auto-generated Term Validation section, not haptoglobin (verified by grepping bare-HP occurrences: all are on lines 568 and 1120-1139, inside that section). Identity otherwise confirms: LIG1 dominant, report OMIM 619774 == MONDO xref OMIM:619774. AR=4 is the autosomal-recessive abbreviation; BLM=2 and PCNA=2 are legitimate mentions (Bloom syndrome as the historical differential, PCNA as LIG1's binding partner). Proceeded on that basis. GENEREVIEWS. No GeneReviews chapter exists. PubMed search '(DNA ligase I deficiency OR LIG1 deficiency OR immunodeficiency 96) AND GeneReviews[All Fields]' returned 0 results. The phenotype baseline is therefore the primary literature (Maffucci 2018 JCI, the 1992 index reports, the 2022 and 2024 case reports) plus the IUIS 2022 classification table, and this is recorded in the entry's notes. REFERENCES USED. PMID:30395541 (Maffucci 2018, disease-defining series, full text), PMID:1351188 (Webster 1992 Lancet, index patient), PMID:1581963 (Barnes 1992, 46BR biochemistry), PMID:36341401 (2022 Omenn-like SCID case), PMID:38896336 (2024 A624T SCID case, with the aggregate table of all reported patients), PMID:39510190 (2024 rare-variant biochemistry), PMID:31630206 (ligase deficiency review), PMID:30725883 (chromosome instability syndromes), PMID:35748970 (IUIS 2022 classification), PMID:11896201 (Bentley 2002 Lig1-null mouse, taken from the DR report's key-reference list). All fetched with 'just fetch-reference'; none hand-written. NOT USED, AND WHY. PMID:42527943 (2026 cyclosporine single-case report, further compound heterozygous LIG1 children) was fetched and PubMed exposes no abstract or full text for it - the cache is content-empty - so no exact-quote snippet is obtainable and nothing in the entry rests on it. Its existence is recorded in the entry's notes so the patient counts read as a floor for the 1992-2024 window rather than as a current total, and its cache file was pruned rather than committed. PMID:33087274 (Human DNA ligases in replication and repair) was fetched, not cited, and pruned. The DR report's HPO frequency table (n/N per phenotype) was read and deliberately not transcribed: with eight published patients an HPO frequency band implies precision the literature does not have, so no phenotype carries 'frequency:'. The DR report gives MedGen as C5676930, which is the UMLS CUI; MONDO's actual MedGen xref is 1810465, and the corrected identifiers are what the entry records. MODELING DECISIONS. Eight-node pathophysiology chain from biallelic hypomorphic LIG1 alleles through failed Okazaki-fragment ligation and abortive ligation, to persistent nicks and replication-associated breaks, to genomic instability, branching into lymphoid, erythroid and somatic-hypermutation arms. The edge from the cellular damage phenotype to the lymphoid phenotype is deliberately INDIRECT_UNKNOWN_INTERMEDIATES and cited to PMID:31630206, which states that the cause of the immunodeficiency in DNA ligase I deficiency is not known - this is the central open question and is also carried as a KNOWLEDGE_GAP discussion. functional_impact_category is PARTIAL_LOSS_OF_FUNCTION, not LOSS_OF_FUNCTION, because no reported genotype is a double null. No conforms_to was declared: genome_instability_mutation and dna_repair_synthetic_lethality are cancer-facing and genomic_instability_aging is aging-facing, and none of their node chains is what this constitutional replication defect produces; the reasoning is recorded in the entry notes. mappings carries an NCIT exactMatch to NCIT:C122658 (DNA Ligase I Deficiency); no ICD-10-CM or ICD-11 mapping is asserted because the closest codes are unspecified-immunodeficiency codes. Five discussions record real open questions, including the 2024 rare-variant work that makes the catalytic-efficiency-versus-abortive-ligation question answerable. The Lig1-null mouse is curated with a PARTIALLY_RECAPITULATES and a RECAPITULATES link plus a REFUTE evidence item for the R771W knock-in, because both models fail to reproduce the human immune phenotype and that failure is informative. PATIENT COUNTS. Corrected mid-curation against the aggregate table in PMID:38896336: eight published patients (1992 index + 5 in Maffucci 2018 + 1 in 2022 + 1 in 2024), four transplanted, four with entirely normal growth, seven of eight with normal mentation. An earlier draft said nine and was wrong. VALIDATION RUN AND READ TO COMPLETION. 'just validate' pass; 'just validate-terms' pass; 'just count-verified-snippets' 96/96 verified against cached references; 'just check-duplicate-keys', 'just check-entity-refs', 'just check-causal-targets', 'just check-qualifier-terms' (0 qualifier terms in this entry), 'just check-enum-values' all OK; 'just check-folded-hyphens', 'just check-snippet-length', 'just check-title-snippets', 'just check-snippet-grading', 'just check-reference-titles' all OK with no new baseline entries; 'just check-environmental-evidence' OK (both new exposures carry entry-level evidence, no waiver used); 'just check-not4curation' OK; 'just check-source-defect-claims' reports nothing for this file. 'just normalize-cache' and 'just check-term-cache-integrity' clean. 'just validate-disorders kb/disorders/Immunodeficiency_96.yaml' passed end to end (schema, terms, references). No DOI-keyed evidence is used, so --unskip-prefix DOI was not needed. CACHE NOTE. cache/go/terms.csv gains a row for GO:0006266 'obsolete DNA ligation'. That row was written by 'just validate-terms' during the draft in which I had bound the now-obsolete term, and it is left in place rather than hand-deleted: it is a correct, tool-derived label row, hand-editing cache rows is against the repository contract, and the row is useful - a future curator reaching for GO:0006266 now gets a cache hit telling them it is obsolete. The entry itself does not reference it. Every other cache addition (GO:0033567, GO:0003910, HP:0500270, MONDO:0030693, NCIT:C122658, NCIT:C15409 and the matching enum-membership rows) is a term this entry binds. CL and ECTO terms used here were already cached, so those files are untouched.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2 citations 2026-09-07T17:12:21.402077

1. Disease Information

Overview. IMD96 is a Mendelian, autosomal recessive DNA-repair/DNA- replication defect presenting as an immunodeficiency. It results from partial deficiency of DNA ligase I. Onset of recurrent, usually viral, respiratory infections occurs in infancy/early childhood; gastrointestinal and urinary tract infections also occur. (Source: OMIM/MONDO disease definition; human clinical — Maffucci 2018, PMID 30395541.)
Key identifiers.
MONDO: MONDO:0030693 (immunodeficiency 96)
OMIM (phenotype): #619774
OMIM (gene LIG1): 126391
DOID: DOID:0061066
MedGen: C5676930 · UMLS: C5676930
Orphanet: No dedicated ORPHA code is firmly established for "IMD96"; the entity historically overlaps "DNA ligase I deficiency." (Not confidently available — flag for curator verification.)
ICD-10: D84.9 (Immunodeficiency, unspecified) / D80.x (predominantly antibody defects) as closest available codes; ICD-11: 4A00.x (primary immunodeficiencies). No IMD96-specific code. (Approximate.)
MeSH: No specific descriptor; nearest terms "Ligases"/"DNA Ligase ATP" and "Immunologic Deficiency Syndromes."
Synonyms / alternative names: IMD96; "immunodeficiency, autosomal recessive due to LIG1 deficiency"; DNA ligase I deficiency; DNA ligase 1 deficiency; the index cell line/patient is historically referred to as 46BR.
Data provenance: Aggregated disease-level knowledge derived from a small number of individual patient case reports (n ≈ 6) plus biochemical and mouse-model studies — not from large EHR/registry cohorts.

2. Etiology

Primary cause — genetic: Biallelic (homozygous or compound heterozygous) pathogenic variants in LIG1. Alleles are amorphic (null-like) or hypomorphic with residual activity; genotype severity tracks clinical/immunologic severity (human clinical/in vitro — Maffucci 2018, PMID 30395541; Barnes 1992, PMID 1581963).
Genetic risk factors: The disease is monogenic and fully genetically determined; the only "risk factor" is inheritance of two defective LIG1 alleles. Consanguinity and being from a kindred segregating LIG1 variants raise recurrence risk (AR inheritance). No established common-variant susceptibility loci or modifier genes are reported.
Environmental risk factors: No environmental cause. However, because cells are hypersensitive to DNA-damaging agents, exposure to genotoxins/UV/ionizing radiation/alkylating chemotherapeutics may aggravate cellular pathology (in vitro — Barnes 1992, PMID 1581963). Photosensitivity is clinically observed.
Protective factors: Retention of residual LIG1 catalytic activity (hypomorphic rather than null alleles) is protective — it explains survival and milder phenotypes, since complete loss is embryonic-lethal in mouse (model organism — Bentley 2002, PMID 11896201). No dietary/lifestyle protective factors are established.
Gene–environment interactions: Genotoxic environmental exposures interact with the underlying repair defect (cells show hypersensitivity to a variety of DNA-damaging agents), plausibly increasing mutation load and cancer risk (in vitro — Barnes 1992, PMID 1581963). Direct GxE quantification is unavailable.

3. Phenotypes

Frequencies below are the exact n/N from the official HPO annotation of OMIM:619774 (sources: PMID 30395541 [Maffucci cohort] and PMID 1581963 [46BR index patient]). Because the total described cohort is ~6 patients, "n/N" is the most precise frequency obtainable.

HPO annotation table (curated, with frequencies): | HPO term | ID | Frequency | Source | |---|---|---|---| | Recurrent infections | HP:0002719 | 5/5 | PMID:30395541 | | Decreased circulating IgG | HP:0004315 | 6/6 | PMID:30395541, 1581963 | | Decreased circulating IgA | HP:0002720 | 6/6 | PMID:30395541, 1581963 | | Decreased circulating IgM | HP:0002850 | 5/5 | PMID:30395541 | | Increased mean corpuscular volume (macrocytosis) | HP:0005518 | 5/5 | PMID:30395541 | | Increased γδ T-cell proportion | HP:0500270 | 4/4 | PMID:30395541 | | Childhood onset | HP:0011463 | 3/5 | PMID:30395541 | | Infantile onset | HP:0003593 | 2/5 | PMID:30395541 | | Multicystic kidney dysplasia | HP:0000003 | 2/5 | PMID:30395541 | | Eczematoid dermatitis | HP:0000964 | 1/5 | PMID:30395541 | | Recurrent lower respiratory tract infections | HP:0002783 | 1/1 | PMID:1581963 | | Recurrent otitis media | HP:0000403 | 1/1 | PMID:1581963 | | Growth delay | HP:0001510 | 1/1 | PMID:1581963 | | Motor delay | HP:0001270 | 1/1 | PMID:1581963 | | Conjunctival telangiectasia | HP:0000524 | 1/1 | PMID:1581963 | | Abnormal T-cell proliferation | HP:0031379 | 1/1 | PMID:1581963 | | Intellectual disability (ABSENT) | HP:0001249 | 0/5 | PMID:30395541 | | Autosomal recessive inheritance | HP:0000007 | — | PMID:1581963 |

Narrative detail follows.

Infectious / immunologic (clinical signs & laboratory abnormalities) - Recurrent respiratory infections, usually viral — infancy/early-childhood onset; core presenting feature. HPO: Recurrent respiratory infections (HP:0002205); Recurrent viral infections (HP:0004429). - Gastrointestinal infections / diarrhea — HP: Chronic diarrhea (HP:0002028); Recurrent gastrointestinal infections (HP:0004798). - Urinary tract infections — HP:0000010. - Hypogammaglobulinemia (laboratory) — reduced immunoglobulins across isotypes: decreased IgG (HP:0004315, 6/6), decreased IgA (HP:0002720, 6/6), decreased IgM (HP:0002850, 5/5); near-universal antibody deficiency (Maffucci 2018). - Lymphopenia (laboratory) — HP:0001888. - Increased circulating γδ T cells (laboratory; distinctive) — HP: Abnormal proportion of gamma-delta T cells/Abnormal T cell subset distribution (HP:0011848 / HP:0011840). - Combined immunodeficiency in severe cases — HP:0005387 (severe combined immunodeficiency spectrum); severe end required HSCT.

Hematologic - Erythrocyte macrocytosis (laboratory; distinctive) — HP: Macrocytic anemia/Increased mean corpuscular volume (HP:0001972 / HP:0005518).

Other organ involvement / dermatologic / renal - Multicystic kidney dysplasia — HP:0000003 (2/5; Maffucci 2018) — notable extra-immune feature. - Eczematoid dermatitis — HP:0000964 (1/5; Maffucci 2018). - Conjunctival telangiectasia — HP:0000524 (1/1; 46BR) — mimics ataxia-telangiectasia (differential-diagnosis clue). - Recurrent otitis media — HP:0000403 (1/1; 46BR).

Growth / neurologic / neoplastic (from index patient, 46BR) - Growth retardation / growth delay — HP:0001510 (1/1; Webster/Barnes 1992). - Motor delay — HP:0001270 (1/1; 46BR). Intellectual disability is ABSENT (HP:0001249, 0/5) — helps distinguish from ataxia-telangiectasia. - Cutaneous photosensitivity / sun sensitivity — HP:0000992 (Webster 1992). - Predisposition to malignancy — lymphoma — HP:0002665 (Lymphoma); the index patient died at 19 with lymphoma (Webster 1992, PMID 1351188).

Phenotype characteristics. Age of onset: infancy/early childhood (some features, e.g., growth retardation, congenital/early). Severity: variable (mild isolated antibody deficiency → combined immunodeficiency). Progression: chronic, with risk of progressive immune compromise and late malignancy. Frequency among affected individuals: infections, hypogammaglobulinemia, lymphopenia, γδ-T-cell increase and macrocytosis were seen in most reported patients (small n).

Quality-of-life impact. Recurrent infections and, in severe cases, need for immunoglobulin replacement or HSCT substantially affect daily functioning; malignancy risk and growth impairment add long-term burden. No formal EQ-5D/SF-36 data exist for this ultra-rare disorder.

4. Genetic / Molecular Information

Causal gene: LIG1 — DNA ligase 1. HGNC:6598; NCBI Gene 3978; Ensembl ENSG00000105486; OMIM gene 126391; UniProt P18858. Locus 19q13.33 (GRCh38 chr19:48,115,444–48,170,654, minus strand). (Computational/database — MyGene/Ensembl; MONDO xrefs.)
Pathogenic variants.
Variant class/type: Predominantly missense hypomorphic alleles in the conserved catalytic domain, plus frameshift/null alleles. The index 46BR patient was compound heterozygous for p.Glu566Lys (c.1696G>A) and p.Arg771Trp (c.2311C>T) (NM_000234.3); p.Arg771 lies in the adenylation/AMP-binding active-site pocket, and p.Glu566Lys behaves as a near-null (Barnes 1992, PMID 1581963; Webster 1992, PMID 1351188). Maffucci 2018 expanded the spectrum across 3 kindreds. Additional ClinVar Pathogenic/Likely-pathogenic loss-of-function alleles include c.1244del (p.Thr415fs) and c.2444del (p.Leu815fs). (Database — ClinVar.)
Classification (ACMG/AMP): Reported disease alleles are pathogenic / likely pathogenic (e.g., p.Glu566Lys = Pathogenic in ClinVar), supported by segregation, functional (enzymatic) assays, and cellular repair-deficiency phenotypes.
Functional consequence: Loss of function — amorphic or hypomorphic alleles with variably decreased ligase enzymatic activity and a strongly reduced ability to form the enzyme–adenylate intermediate, leading to premature release of unligated adenylated DNA (in vitro — Barnes 1992, PMID 1581963; Maffucci 2018, PMID 30395541).
Allele frequency: Individual pathogenic alleles are ultra-rare in gnomAD; biallelic loss is extremely rare (carrier frequency not formally established). gnomAD v2.1.1 gene constraint shows LIG1 is not haploinsufficient (pLI≈0.004; oe_lof≈0.29, 90% CI 0.19–0.45; missense Z≈0.82), i.e. heterozygous loss is tolerated — consistent with recessive inheritance and healthy obligate carriers (index patient's mother and two brothers).
Somatic vs germline: Germline, inherited.
Modifier genes: None established; residual LIG1 activity itself is the main modifier of severity. Functional redundancy from DNA ligase III (LIG3)/XRCC1 in some repair contexts may partially compensate (biological rationale).
Epigenetic information: No disease-specific epigenetic signatures reported.
Chromosomal abnormalities: None; IMD96 is a single-gene point-mutation disorder (chromosome 19). No aneuploidy/translocation etiology.

5. Environmental Information

Environmental factors: Not causal. Cellular hypersensitivity to DNA-damaging agents (UV, ionizing radiation, alkylating agents) means such exposures are biologically relevant aggravators (in vitro — Barnes 1992, PMID 1581963); photosensitivity is clinically evident.
Lifestyle factors: No established lifestyle contributors; sun protection is prudent given photosensitivity.
Infectious agents: Infections are a consequence of immunodeficiency, not a cause. Reported/expected pathogens: respiratory viruses predominate; bacterial respiratory, gastrointestinal and urinary infections also occur.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic hypomorphic/amorphic LIG1 mutations lead to reduced or absent functional DNA ligase I protein / enzymatic activity (in vitro — Maffucci 2018; Barnes 1992).
Impaired formation of the enzyme–adenylate intermediate results in inefficient nick sealing and premature release of unligated, adenylated DNA (in vitro — Barnes 1992, PMID 1581963; Maffucci 2018, PMID 30395541).
This leads to retarded joining of Okazaki fragments during lagging-strand DNA replication and incomplete excision repair (in vitro — Barnes 1992).
Which results in accumulation of DNA replication intermediates, unligated nicks, replication stress and genome instability (model organism — Bentley 2002, PMID 11896201; inferred to operate similarly in human hematopoietic precursors).
Genome instability + replication stress lead to reduced proliferation and survival of rapidly dividing cells, disproportionately affecting lymphoid and erythroid precursors (model organism — Bentley 2002; inferred for human lineage-specific effects).
Branch A (lymphoid): results in lymphopenia, impaired B-cell/antibody output (hypogammaglobulinemia), skewed T-cell subsets with increased γδ T cells → recurrent viral/bacterial infections and combined immunodeficiency.
Branch B (erythroid): results in impaired erythropoiesis with erythrocyte macrocytosis (phenocopying impaired DNA synthesis).
Branch C (genome-wide, long-term): cumulative genome instability leads to cancer predisposition (lymphoma), and in skin, UV-hypersensitivity contributes to photosensitivity; systemic replication impairment contributes to growth retardation (human clinical — Webster 1992, PMID 1351188).

Category detail supporting these steps - Molecular pathways / processes: DNA replication (lagging-strand Okazaki fragment maturation), long-patch base excision repair, nucleotide/excision repair completion. GO: DNA ligation (GO:0006266), DNA replication (GO:0006260), base-excision repair (GO:0006284), DNA repair (GO:0006281), lagging strand elongation (GO:0006273). - Cellular processes: Replication stress, cell-cycle impairment, reduced proliferation/survival of precursors, genome instability. GO: cellular response to DNA damage stimulus (GO:0006974). - Protein dysfunction: Loss/hypomorphic DNA ligase I (UniProt P18858, 919 aa; ATP-dependent ligase; PCNA-interacting replicative ligase). Domain map: N-terminal disordered regulatory region (1–270) carrying the PCNA-interacting/ replication-factory-targeting sequence and CDK phosphosites; central adenylation (catalytic) domain with active-site Lys568 (forms the N6-AMP-lysine enzyme–adenylate intermediate) and AMP/ATP-binding residues at 566, 573, 621, 720, 725, 744; C-terminal OB-fold DNA-binding domain. Disease variants map directly onto catalysis: p.Glu566Lys alters an AMP-binding residue adjacent to catalytic Lys568 (abolishing adenylation — matching the measured loss of enzyme–adenylate formation), and p.Arg771Trp disrupts the OB-fold DNA/nick-binding surface. GO cellular component: nucleus (GO:0005634), replication fork (GO:0005657). PDB: 1X9N (human LIG1–DNA complex). (Database — UniProt/PDB; in vitro — Barnes 1992.) - Immune system involvement: Immunodeficiency (combined + humoral) from impaired lymphocyte development/proliferation and antibody production. - Tissue-damage mechanism: Genotoxic stress/genome instability rather than inflammation or ischemia. - Cell types (CL): hematopoietic stem/progenitor cell (CL:0000037), T cell (CL:0000084) incl. γδ T cell (CL:0000798), B cell (CL:0000236), erythroid progenitor (CL:0000038). - Molecular profiling: No large omics datasets; functional biochemistry (ligase/adenylation assays) and cellular DNA-damage survival assays are the principal readouts (Barnes 1992; Maffucci 2018).

7. Anatomical Structures Affected

Organ/system level: Immune (hematolymphoid) system is primary — bone marrow, thymus, lymphoid tissues (UBERON:0002405 immune system; UBERON:0002371 bone marrow; UBERON:0002370 thymus). Secondary involvement: respiratory tract (recurrent infection; UBERON:0001004), gastrointestinal tract (UBERON:0001555), urinary tract (UBERON:0011143), kidney (UBERON:0002113; multicystic kidney dysplasia in 2/5 — developmental/structural involvement), skin (UBERON:0002097; eczema, photosensitivity, conjunctival telangiectasia), and systemic growth.
Tissue/cell level: Hematopoietic tissue; lymphocytes (T incl. γδ, B), erythroid lineage; skin epithelium (UV sensitivity). CL terms as in §6.
Subcellular level: Nucleus (GO:0005634) — site of DNA replication/repair where DNA ligase I acts (GO cellular component: replication fork, GO:0005657; nuclear replication fork, GO:0043596).
Localization / lateralization: Systemic (not lateralized); infections and manifestations are bilateral/diffuse.

8. Temporal Development

Onset: Infancy/early childhood for infections; growth retardation and photosensitivity may be evident early. Pattern: chronic/insidious with recurrent acute infective episodes.
Progression: Variable — from stable mild antibody deficiency to progressive combined immunodeficiency. Genome instability confers late-onset malignancy risk (lymphoma in the index patient at age 19).
Course & duration: Chronic, lifelong. Recurrent-infection pattern; severe cases progress to transplant dependence.
Remission / critical windows: No spontaneous remission; HSCT can be curative for the immune defect. Early diagnosis before severe infections or malignancy is the key intervention window.

9. Inheritance and Population

Inheritance: Autosomal recessive (homozygous or compound heterozygous LIG1); parents are typically asymptomatic carriers (Webster 1992: one mutation inherited from the mother and also present in two healthy brothers — carriers).
Penetrance / expressivity: Presumed high penetrance for biallelic damaging genotypes but markedly variable expressivity/severity, correlating with residual ligase activity (Maffucci 2018, PMID 30395541).
Genetic anticipation: Not applicable (not a repeat-expansion disorder).
Germline mosaicism / founder effects: None reported.
Consanguinity: Relevant, as for AR disorders (homozygous cases).
Carrier frequency: Not established; individual alleles ultra-rare in gnomAD.
Epidemiology: Ultra-rare — only ~6 molecularly confirmed patients described (1 index case + 5 in Maffucci 2018). Prevalence/incidence per 100,000 are not calculable and are effectively unknown/<1 in 10^6.
Demographics: Reported across more than one kindred/ethnicity; no strong sex predilection established (index case female). No defined geographic focus.

10. Diagnostics

Laboratory tests (LOINC-type): CBC showing erythrocyte macrocytosis (elevated MCV) and lymphopenia; serum immunoglobulins showing hypogammaglobulinemia; specific antibody responses (impaired).
Immunophenotyping (flow cytometry): Increased proportion of circulating γδ T cells, altered T-cell subsets; a distinctive combination with macrocytosis and hypogammaglobulinemia should prompt LIG1 testing (Maffucci 2018).
Functional/cellular assays (in vitro): Cellular hypersensitivity to DNA-damaging agents; retarded Okazaki-fragment joining; reduced DNA ligase I adenylation/enzymatic activity — historically used to characterize 46BR (Barnes 1992, PMID 1581963).
Biomarkers: The triad (macrocytosis + γδ-T-cell increase + hypogammaglobulinemia) is a useful clinical flag; premature release of unligated adenylated DNA is a research biochemical marker.
Genetic testing (primary confirmatory): WES/WGS or IEI gene panels including LIG1; confirm biallelic variants by Sanger. Single-gene LIG1 sequencing where phenotype is suggestive. CMA/karyotype/FISH generally uninformative (point-mutation disorder).
Clinical criteria / differential diagnosis: Distinguish from Bloom syndrome (BLM; the index patient resembled Bloom's but lacked BLM mutation — Webster 1992), other DNA-repair/genome-instability syndromes (Fanconi anemia, ataxia-telangiectasia, Nijmegen breakage syndrome), common variable immunodeficiency, and combined immunodeficiencies. Macrocytosis + γδ-T-cell increase help separate IMD96 from typical CVID.
Screening: Cascade/carrier testing within affected families; no population newborn screening.

11. Outcome / Prognosis

Severity spectrum: From mild antibody deficiency (favorable with Ig replacement) to severe combined immunodeficiency requiring HSCT (Maffucci 2018).
Mortality/survival: No formal survival statistics (ultra-rare). Severe, untreated disease carries risk of fatal infection; the index patient died at age 19 of lymphoma (Webster 1992), illustrating malignancy-related mortality.
Morbidity: Recurrent infections, growth retardation, treatment burden (immunoglobulin therapy, transplant), and long-term cancer risk.
Prognostic factors: Residual LIG1 enzymatic activity / genotype is the key determinant; earlier diagnosis and definitive therapy (HSCT) improve immune outcomes. No validated QoL instruments for this disease.

12. Treatment

No disease-specific approved drug exists; management follows inborn-errors-of- immunity principles. - Supportive / pharmacotherapy: Immunoglobulin replacement therapy (IVIG/ SCIG) for hypogammaglobulinemia; antimicrobial prophylaxis and aggressive treatment of infections. NCIT: Intravenous Immunoglobulin Therapy (approx.), Antibiotic Therapy. - Definitive/advanced therapy: Allogeneic hematopoietic stem cell transplantation (HSCT) for the severe combined-immunodeficiency end of the spectrum (used in Maffucci 2018 cohort). NCIT: Hematopoietic Stem Cell Transplantation (C15431). Gene therapy is conceptually plausible but not reported/established for IMD96. - Caution — genotoxic agents: Given DNA-repair deficiency and cellular hypersensitivity, use radiation and alkylating/DNA-damaging chemotherapeutics with caution (e.g., in transplant conditioning or any cancer therapy) (in vitro rationale — Barnes 1992). - Pharmacogenomics / personalized: Genotype (residual ligase activity) informs whether Ig replacement suffices vs. need for HSCT. - Treatment outcomes / adverse events: HSCT can restore immune function; standard transplant risks apply, potentially heightened by conditioning-related genotoxic sensitivity. Formal response-rate data are lacking (small n).

13. Prevention

Primary prevention: Not preventable (germline). Genetic counseling for AR recurrence risk (25% per pregnancy for carrier couples); carrier/cascade testing in affected families; prenatal or preimplantation genetic testing where a familial variant is known.
Secondary prevention: Early recognition of the lab triad → early molecular diagnosis → early institution of Ig replacement/prophylaxis or HSCT before irreversible complications; malignancy surveillance given lymphoma risk.
Tertiary prevention: Infection prophylaxis, immunizations as appropriate for immune status, sun protection (photosensitivity), avoidance of unnecessary genotoxic exposures.
Public health / behavioral: No population-level measures beyond counseling.

14. Other Species / Natural Disease

Taxonomy / orthologs: LIG1 is highly conserved. Mouse Lig1 (NCBI Gene 16881; NCBI Taxon 10090); orthologs across vertebrates and lower eukaryotes (CDC9 in S. cerevisiae). Evolutionary conservation of the replicative-ligase function is strong.
Natural disease in animals: No well-characterized spontaneous LIG1 immunodeficiency reported in companion animals/wildlife (OMIA — none prominent).
Comparative biology: Complete loss is embryonic lethal in mouse (Bentley 2002, PMID 11896201), underscoring conserved essentiality; human patients survive due to residual activity of hypomorphic alleles — a key cross-species contrast.
Transmission / zoonosis: Not applicable (non-infectious genetic disease).

15. Model Organisms

Mouse (Mus musculus, NCBI Taxon 10090):* Lig1 knockout — two independent null alleles; embryos develop normally to mid-gestation then die from a specific hematopoietic (fetal-liver) defect that is a quantitative proliferation deficiency rather than a lineage block; Lig1-null fibroblasts accumulate replication intermediates and show increased genome instability* despite grossly normal repair activity (Bentley 2002, PMID 11896201). MGI-type resources apply.
Cellular models (in vitro): The human 46BR fibroblast strain (index patient) and engineered LIG1-deficient cell lines demonstrating chemical/ radiation repair defects and reduced ligase activity (Barnes 1992, PMID 1581963; Maffucci 2018, PMID 30395541).
Phenotype recapitulation: Mouse null captures the hematopoietic proliferation defect and genome instability central to human pathology but is more severe (lethal) and does not model the survivable, variable human immunodeficiency (embryonic lethality precludes study of mature adaptive immunity). Human hypomorphic cell lines better model the partial-deficiency disease.

Supported vs. refuted hypotheses

Supported: IMD96 = autosomal recessive LIG1 (DNA ligase I) deficiency (MONDO:0030693 / OMIM 619774). Mechanism = impaired Okazaki-fragment ligation + excision-repair completion → genome instability → lymphoid/erythroid proliferation failure. Characteristic labs: hypogammaglobulinemia, lymphopenia, increased γδ T cells, erythrocyte macrocytosis. HSCT curative for severe cases.
Supported (residue-level mechanism): disease variants map onto the LIG1 catalytic pocket — p.Glu566Lys hits an AMP-binding residue adjacent to active-site Lys568 (abolishing the enzyme–adenylate step measured by Barnes 1992), while p.Arg771Trp disrupts the OB-fold DNA-binding domain — a direct structural explanation for the loss-of-function biochemistry. gnomAD confirms LIG1 is not haploinsufficient (pLI≈0.004), consistent with recessive inheritance and healthy carriers.
Supported (phenotype frequencies): curated HPO annotations give near-complete penetrance for decreased IgG/IgA (6/6), decreased IgM (5/5), macrocytosis (5/5), increased γδ T cells (4/4) and recurrent infections (5/5); intellectual disability is explicitly absent (0/5), and renal (multicystic kidney dysplasia 2/5) plus dermatologic features broaden the spectrum.
Refuted / corrected: Initial assumption that "Immunodeficiency 96" was the REL/c-Rel disorder was wrong — c-Rel deficiency is Immunodeficiency 92 (IMD92). This was corrected by resolving MONDO:0030693 to LIG1.
Refuted historically: The index patient was NOT Bloom syndrome despite clinical resemblance (Webster 1992) — a distinct genetic entity.

Limitations & future directions

Ultra-rare with ~6 molecularly confirmed patients; frequencies, penetrance, survival and QoL are not quantifiable. Orphanet/ICD-specific codes are uncertain and need curator confirmation.
No omics (transcriptomic/proteomic/metabolomic) disease datasets; no dedicated gene therapy program.
Future work: define exact recurrent LIG1 alleles and genotype–phenotype/ residual-activity correlations; systematic malignancy-risk surveillance; conditional/hypomorphic mouse or patient-iPSC models to study lineage-specific immune defects and to test safer (reduced-genotoxicity) transplant conditioning.

Key references (PMID)

30395541 — Maffucci et al. 2018, J Clin Invest: biallelic LIG1 mutations underlie a spectrum of immune deficiencies (5 patients/3 kindreds). (Human clinical + in vitro.)
1351188 — Webster et al. 1992, Lancet: growth retardation and immunodeficiency with LIG1 mutations (index patient; lymphoma at 19). (Human clinical.)
1581963 — Barnes et al. 1992, PNAS: LIG1 mutations in 46BR; Okazaki- fragment/excision-repair defect; reduced enzyme-adenylate formation. (In vitro/ biochemical.)
11896201 — Bentley et al. 2002: Lig1-null mouse; embryonic-lethal hematopoietic proliferation defect and genome instability. (Model organism.)

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	2
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	56
Resolved	53
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	30
Terms named correctly	14
Terms named as a different term	7
Terms whose name is worth a second look	9

Terms the report names something else

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

HP:0000003 (2 mentions) - the report calls it "Multicystic kidney dysplasia", "2/5; Maffucci 2018"; HP calls it Multicystic kidney dysplasia
HP:0000964 (2 mentions) - the report calls it "Eczematoid dermatitis", "1/5; Maffucci 2018"; HP calls it Eczematoid dermatitis
HP:0000403 (2 mentions) - the report calls it "Recurrent otitis media", "1/1; 46BR"; HP calls it Recurrent otitis media
HP:0001510 (2 mentions) - the report calls it "Growth delay", "1/1; Webster/Barnes 1992"; HP calls it Growth delay
HP:0001270 (2 mentions) - the report calls it "Motor delay", "1/1; 46BR"; HP calls it Motor delay
HP:0000524 (2 mentions) - the report calls it "Conjunctival telangiectasia", "1/1; 46BR"; HP calls it Conjunctival telangiectasia
HP:0000992 (1 mention) - the report calls it "Webster 1992"; HP calls it Cutaneous photosensitivity

Obsolete terms

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

GO:0006266 (obsolete DNA ligation) (1 mention)

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:

HP:0004315 (2 mentions) - the report calls it "Decreased circulating IgG"; HP calls it Decreased circulating IgG concentration, and lists "Decreased circulating IgG level" among its other names
HP:0002720 (2 mentions) - the report calls it "Decreased circulating IgA"; HP calls it Decreased circulating IgA concentration, and lists "Decreased circulating IgA level" among its other names
HP:0002850 (2 mentions) - the report calls it "Decreased circulating IgM"; HP calls it Decreased circulating IgM concentration
HP:0005518 (2 mentions) - the report calls it "Increased mean corpuscular volume (macrocytosis)"; HP calls it Increased mean corpuscular volume
HP:0500270 (1 mention) - the report calls it "Increased γδ T-cell proportion"; HP calls it Increased gamma-delta T cell proportion
HP:0001249 (2 mentions) - the report calls it "Intellectual disability (ABSENT)"; HP calls it Intellectual disability
GO:0006266 (1 mention) - the report calls it "DNA ligation"; GO calls it obsolete DNA ligation
GO:0005634 (2 mentions) - the report calls it "nucleus", "Nucleus", "Subcellular level: Nucleus"; GO calls it nucleus, and lists "cell nucleus" among its other names
UBERON:0011143 (1 mention) - the report calls it "urinary tract"; UBERON calls it upper urinary tract

Terms named inconsistently

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

HP:0000003 - called "Multicystic kidney dysplasia", "2/5; Maffucci 2018"
HP:0000964 - called "Eczematoid dermatitis", "1/5; Maffucci 2018"
HP:0000403 - called "Recurrent otitis media", "1/1; 46BR"
HP:0001510 - called "Growth delay", "1/1; Webster/Barnes 1992"
HP:0001270 - called "Motor delay", "1/1; 46BR"
HP:0000524 - called "Conjunctival telangiectasia", "1/1; 46BR"
GO:0005634 - called "nucleus", "Nucleus", "Subcellular level: Nucleus"

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.

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Key references (PMID)

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver