Hyper-IgM syndrome type 5 (HIGM5) is a primary antibody deficiency caused by biallelic loss-of-function variants in UNG, encoding uracil-DNA glycosylase. It is one of the B-cell-intrinsic immunoglobulin class-switch recombination (CSR) deficiencies and shares the hyper-IgM serum signature with the other forms: normal or elevated IgM with severely reduced IgG and IgA (and typically low IgE), normal numbers of circulating B cells, and recurrent bacterial infection with lymphoid hyperplasia. The lesion sits one step downstream of activation-induced cytidine deaminase (AID). AID deaminates cytosine to uracil in single-stranded DNA at the immunoglobulin switch and variable regions; the nuclear isoform of UNG (UNG2) then excises that uracil, generating the abasic sites that downstream repair enzymes convert into the switch-region DNA breaks required for CSR. When UNG is absent, unstable, or mistargeted, the AID-generated uracil is not efficiently removed, so CSR fails at a DNA precleavage step and the somatic-hypermutation spectrum is distorted rather than abolished. SCOPE AND CONTRAST. The defect is B-cell intrinsic, so — like AID deficiency (HIGM2) and unlike the CD40L (HIGM1) and CD40 (HIGM3) forms — T-cell and myeloid CD40 signalling is preserved and patients are not characteristically susceptible to the opportunistic infections of the CD40-axis defects. The IUIS 2024 classification records this: UNG deficiency sits in Table 3 (predominantly antibody deficiencies), in the hyper-IgM section, whereas CD40LG and CD40 deficiency sit in Table 1 (combined immunodeficiencies). Only a handful of molecularly confirmed patients have been reported, so frequencies in this entry are qualitative; the deepest evidence is the original three-patient series and the biochemical studies of those patients' B-cell lines, supplemented by Ung-knockout mouse and engineered-B-cell data that are noted as such.
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Conditions with similar clinical presentations that must be differentiated from Hyper-IgM Syndrome Type 5:
name: Hyper-IgM Syndrome Type 5
creation_date: "2026-10-18T00:00:00Z"
category: Mendelian
synonyms:
- HIGM5
- UNG hyper-IgM syndrome
- hyper-IgM syndrome 5
- hyper-IgM syndrome due to UNG deficiency
- hyper-IgM syndrome due to uracil N-glycosylase
- uracil-DNA glycosylase deficiency
- immunodeficiency with hyper IgM, type 5
description: >-
Hyper-IgM syndrome type 5 (HIGM5) is a primary antibody deficiency caused by
biallelic loss-of-function variants in UNG, encoding uracil-DNA glycosylase.
It is one of the B-cell-intrinsic immunoglobulin class-switch recombination
(CSR) deficiencies and shares the hyper-IgM serum signature with the other
forms: normal or elevated IgM with severely reduced IgG and IgA (and
typically low IgE), normal numbers of circulating B cells, and recurrent
bacterial infection with lymphoid hyperplasia. The lesion sits one step
downstream of activation-induced cytidine deaminase (AID). AID deaminates
cytosine to uracil in single-stranded DNA at the immunoglobulin switch and
variable regions; the nuclear isoform of UNG (UNG2) then excises that uracil,
generating the abasic sites that downstream repair enzymes convert into the
switch-region DNA breaks required for CSR. When UNG is absent, unstable, or
mistargeted, the AID-generated uracil is not efficiently removed, so CSR fails
at a DNA precleavage step and the somatic-hypermutation spectrum is distorted
rather than abolished.
SCOPE AND CONTRAST. The defect is B-cell intrinsic, so — like AID deficiency
(HIGM2) and unlike the CD40L (HIGM1) and CD40 (HIGM3) forms — T-cell and
myeloid CD40 signalling is preserved and patients are not characteristically
susceptible to the opportunistic infections of the CD40-axis defects. The
IUIS 2024 classification records this: UNG deficiency sits in Table 3
(predominantly antibody deficiencies), in the hyper-IgM section, whereas
CD40LG and CD40 deficiency sit in Table 1 (combined immunodeficiencies).
Only a handful of molecularly confirmed patients have been reported, so
frequencies in this entry are qualitative; the deepest evidence is the
original three-patient series and the biochemical studies of those patients'
B-cell lines, supplemented by Ung-knockout mouse and engineered-B-cell data
that are noted as such.
disease_term:
preferred_term: hyper-IgM syndrome type 5
term:
id: MONDO:0011971
label: hyper-IgM syndrome type 5
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
- Hyper-IgM Syndrome
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
A primary immunodeficiency; Harrison's covers the primary
immunodeficiency diseases in the immunology/rheumatology Part.
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR)
deficiencies, previously termed hyper-IgM syndromes, are genetically
determined conditions characterized by normal or elevated serum IgM
levels and an absence or very low levels of IgG, IgA, and IgE.
explanation: >-
Places the Ig-CSR deficiencies, which include UNG deficiency
(Ig-CSR deficiency 2 in this review), among the genetically determined
immunodeficiency disorders of the immunologic Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
Monogenic autosomal recessive disorder of UNG.
iuis_category:
classification_value: predominantly antibody deficiency
notes: >-
IUIS 2024 phenotypic classification Table 3 (predominantly antibody
deficiencies), section 3 "Severe reduction in serum IgG and IgA with
normal/elevated IgM and normal numbers of B cells, hyper-IgM". The UNG
deficiency row lists UNG, autosomal recessive, OMIM 191525. NOTE THE
CONTRAST: the CD40LG and CD40 hyper-IgM syndromes are NOT in Table 3 —
IUIS places them in Table 1 (combined immunodeficiencies) — because the
CD40 pathway defect impairs T-cell and macrophage activation as well as
B-cell class switching.
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper-IgM"
explanation: >-
The section-3 heading of IUIS 2024 Table 3 (predominantly antibody
deficiencies) that contains the UNG deficiency row, establishing the
IUIS category for this entry.
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased | Enlarged lymph nodes and germinal centers"
explanation: >-
The IUIS 2024 Table 3 UNG deficiency row itself, recording the gene,
autosomal recessive inheritance, the hyper-IgM serum pattern, and the
lymphoid-hyperplasia associated feature.
inheritance:
- name: Autosomal recessive inheritance
description: >-
HIGM5 is inherited as an autosomal recessive trait, caused by biallelic
(homozygous or compound-heterozygous) loss-of-function variants in UNG.
Consanguinity was documented in reported families.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:12958596
reference_title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
recessive mutations of the gene encoding uracil-DNA glycosylase (UNG) are
associated with profound impairment in CSR at a DNA precleavage step and
with a partial disturbance of the SHM pattern in three patients with
hyper-IgM syndrome
explanation: >-
The gene-discovery study establishes recessive UNG mutations as the cause
of the hyper-IgM phenotype.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population-based prevalence estimate for HIGM5 exists; Orphanet lists
prevalence as unavailable. The disease is known from a small number of
molecularly confirmed patients: the original report described three
unrelated patients, and in a molecular survey of 140 hyper-IgM patients
only a single adult male had a UNG mutation. These are referral-based
counts, not denominators, so no rate per 100,000 is asserted.
evidence:
- reference: PMID:15358621
reference_title: "Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1
female); UNG in one adult male; and Btk in 3 boys.
explanation: >-
In a 140-patient hyper-IgM cohort a single patient had a UNG mutation,
illustrating the rarity of HIGM5 relative to the CD40L form.
pathophysiology:
- name: UNG Loss of Function
biological_scale: MOLECULAR
description: >-
Uracil-DNA glycosylase is encoded by UNG, which produces a mitochondrial
isoform (UNG1) and a nuclear isoform (UNG2); UNG2 is induced in activated
germinal-center B cells. It hydrolyses the N-glycosidic bond of uracil in
DNA, initiating base-excision repair by creating an abasic (AP) site.
Biallelic UNG variants abolish or severely reduce this nuclear activity:
truncating alleles yield catalytically dead protein, and the F251S missense
allele produces an enzyme that is active in vitro but mistargeted to
mitochondria and degraded in B cells, leaving only trace residual activity.
This molecular lesion is the single upstream cause of the downstream
class-switch and hypermutation defects.
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
genes:
- preferred_term: UNG
term:
id: hgnc:12572
label: UNG
molecular_functions:
- preferred_term: uracil DNA N-glycosylase activity
term:
id: GO:0004844
label: uracil DNA N-glycosylase activity
modifier: DECREASED
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
downstream:
- target: Failure of Switch-Region Uracil Excision
description: >-
Loss of nuclear UNG removes the enzyme that excises AID-generated uracil
from immunoglobulin switch-region DNA.
evidence:
- reference: PMID:12958596
reference_title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
these data support a model of CSR and SHM in which AID deaminates
cytosine into uracil in targeted DNA (immunoglobulin switch or variable
regions), followed by uracil removal by UNG
- reference: PMID:15967827
reference_title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In B cell lines from hyper-IgM patients carrying UNG mutations, the
single-strand-specific uracil-DNA glycosylase, SMUG1, cannot complement
this function.
explanation: >-
Patient B-cell lines (the same three patients as the gene-discovery
report, not an independent cohort) show the backup glycosylase SMUG1
cannot substitute for lost nuclear UNG.
evidence:
- reference: PMID:15967827
reference_title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the UNG mutations lead to increased accumulation of genomic uracil
explanation: >-
Biochemical study of patient B-cell lines (shared with the discovery
series) confirms functional loss of UNG with accumulation of genomic
uracil.
- name: Failure of Switch-Region Uracil Excision
biological_scale: MOLECULAR
description: >-
AID converts cytosine to uracil in single-stranded DNA at transcribed
switch and variable regions. Without UNG, that uracil is not efficiently
removed. The AID-directed step depends specifically on UNG being recruited
to RPA-coated single-stranded DNA, a function separable from canonical
repair of uracil in double-stranded genomic DNA. The unexcised U:G lesions
propagate into the two downstream antibody-diversification failures.
biological_processes:
- preferred_term: base-excision repair, AP site formation via deaminated base removal
term:
id: GO:0097510
label: "base-excision repair, AP site formation via deaminated base removal"
modifier: DECREASED
downstream:
- target: Impaired Class-Switch Recombination
description: >-
Reduced excision of switch-region uracil yields fewer abasic sites and
the DNA nicks and double-strand breaks CSR requires.
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
the AID-UNG pathway directly targets DNA of switch regions from the Ig
heavy-chain locus to induce the CSR process
explanation: >-
The review places UNG action on switch-region DNA as the step that
initiates class-switch recombination, so loss of uracil excision there
blocks CSR.
- target: Altered Somatic Hypermutation Spectrum
description: >-
Persistence of unexcised U:G lesions skews the point-mutation spectrum
introduced during somatic hypermutation.
evidence:
- reference: PMID:31507588
reference_title: "Repertoire Sequencing of B Cells Elucidates the Role of UNG and Mismatch Repair Proteins in Somatic Hypermutation in Humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with MMR or UNG deficiency have reduced frequency and altered
patterns of SHM in line with a five-pathway model to generate SHM.
explanation: >-
Repertoire sequencing shows an altered SHM pattern in UNG deficiency.
The UNG-specific data come from a single patient within a mixed
MMR/UNG cohort.
evidence:
- reference: PMID:38000394
reference_title: "RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We show that the UNG:RPA interaction plays a crucial role in both CSR and
repair of AID-induced uracil at the Ig loci.
explanation: >-
Engineered B-cell clones show UNG recruitment to RPA-coated ssDNA is
required for CSR and for repair of AID-induced uracil at the Ig loci.
- name: Impaired Class-Switch Recombination
conforms_to: "germinal_center_reaction#Germinal Center Reaction"
biological_scale: CELLULAR
description: >-
The block is at a DNA precleavage step: without efficient uracil excision,
switch regions are not cut, so recombination from Cmu to the downstream
Cgamma, Calpha or Cepsilon constant regions fails. In human UNG deficiency
this failure is profound, more severe than in the Ung-knockout mouse, where
a mismatch-repair backup leaves switching only partly inhibited.
biological_processes:
- preferred_term: isotype switching
term:
id: GO:0045190
label: isotype switching
modifier: DECREASED
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
downstream:
- target: Impaired immunoglobulin class-switch recombination
description: >-
The precleavage block manifests as a measurable failure of in-vitro
class-switch recombination in patient B cells.
- target: Loss of Class-Switched Serum Antibody
description: >-
Failure to switch constant regions prevents production of IgG, IgA and
IgE and leaves IgM as the dominant isotype.
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
In humans, UNG-deficiency results in the hyper IgM syndrome
characterized by recurrent infections, lymphoid hyperplasia, extremely
low IgG, IgA and IgE and elevated IgM.
explanation: >-
The review links UNG deficiency to the switched-isotype deficit with
preserved or raised IgM, which is the output of the CSR block.
- target: Reduced Class-Switched Memory B Cells
description: >-
Cells that fail to complete class switching do not populate the
switched-memory compartment.
evidence:
- reference: PMID:33276124
reference_title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSRD patients showed uniformly absent or markedly reduced switched
memory B cells (IgM-IgD-CD27+).
explanation: >-
In class-switch recombination defects, including UNG deficiency,
switched-memory B cells are absent or markedly reduced.
- target: Germinal Center and Lymphoid Hyperplasia
description: >-
B cells that cannot complete switching keep being driven by antigen,
enlarging germinal centers and lymph nodes.
evidence:
- reference: PMID:15967827
reference_title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
similar to those associated with AID deficiency, including
susceptibility to bacterial infections and lymphoid hyperplasia
explanation: >-
Pairs the CSR-defect phenotype of UNG-deficient patients with lymphoid
hyperplasia, as in AID deficiency. The sentence is the paper's framing
of the patients' clinical picture, not its own experimental result.
evidence:
- reference: PMID:12958596
reference_title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
recessive mutations of the gene encoding uracil-DNA glycosylase (UNG) are
associated with profound impairment in CSR at a DNA precleavage step
explanation: >-
The discovery study localises the CSR block to a DNA precleavage step.
- reference: PMID:12401169
reference_title: "Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Class-switch recombination is substantially, but not totally, inhibited.
explanation: >-
In Ung-knockout mice switching is only partly inhibited; the human defect
is more severe, so the mouse supports the mechanism indirectly rather than
recapitulating the human phenotype.
- name: Altered Somatic Hypermutation Spectrum
biological_scale: MOLECULAR
description: >-
UNG deficiency does not abolish somatic hypermutation but distorts its
spectrum. Unexcised U:G lesions persist and favour replication-associated
G:C transitions, while the loss of abasic-site formation reduces G:C
transversions. In the mouse this shows as a shift to ~95% transitions at
G:C pairs; a single human UNG-deficient repertoire showed the same
directional skew.
biological_processes:
- preferred_term: somatic hypermutation of immunoglobulin genes
term:
id: GO:0016446
label: somatic hypermutation of immunoglobulin genes
modifier: ABNORMAL
evidence:
- reference: PMID:12401169
reference_title: "Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
In ung(-/-) animals, mutations at dC/dG pairs are dramatically shifted
toward transitions (95%), indicating that the generation of abasic sites
(which can induce transversions) has been inhibited.
explanation: >-
The Ung-knockout mouse defines the spectrum shift; the direction is
confirmed in a single human patient (PMID:31507588) but the quantitative
mouse figure is not human data.
- name: Loss of Class-Switched Serum Antibody
biological_scale: ORGANISM
description: >-
The CSR block produces the diagnostic serum profile — severely reduced IgG
and IgA with low IgE and normal or elevated IgM — and leaves patients
unable to mount switched, high-affinity antibody responses to protein and
polysaccharide antigens, impairing opsonization and mucosal defence.
downstream:
- target: Increased circulating IgM level
description: IgM is not converted to downstream isotypes and accumulates.
- target: Decreased circulating IgG concentration
description: Failure to switch to Cgamma abolishes normal IgG production.
- target: Decreased circulating IgA concentration
description: Failure to switch to Calpha abolishes normal IgA production.
- target: Decreased circulating IgE concentration
description: Failure to switch to Cepsilon leaves IgE low or absent.
- target: Impaired specific antibody response
description: >-
Without class switching, antigen-specific IgG responses to vaccines and
neoantigens are poor.
evidence:
- reference: PMID:33276124
reference_title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Antibody response to phage was remarkably decreased with lack of memory
amplification and class-switching in immunized CD40L, UNG deficient, and
NEMO patients.
explanation: >-
UNG-deficient patients immunized with a neoantigen mounted a markedly
decreased antibody response without class switching.
- target: Defective Opsonizing and Mucosal Antibody Defense
description: >-
Loss of switched IgG and secretory IgA removes opsonizing and mucosal
antibody protection against encapsulated bacteria.
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
extremely low IgG, IgA and IgE and elevated IgM
explanation: >-
The review states the hyper-IgM serum profile that defines UNG
deficiency.
- name: Defective Opsonizing and Mucosal Antibody Defense
biological_scale: ORGANISM
description: >-
Lacking switched antibody, patients cannot opsonize or neutralize
bacteria efficiently, producing recurrent bacterial infection. The cited
UNG-specific sources describe this only as recurrent or bacterial
infection; the sinopulmonary pattern and airway sequelae typical of severe
antibody deficiency are expected but not documented in published HIGM5
patients, so they are not recorded as phenotypes here.
downstream:
- target: Recurrent bacterial infections
description: Loss of opsonizing and mucosal antibody leaves bacterial infection uncontrolled.
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
In humans, UNG-deficiency results in the hyper IgM syndrome characterized
by recurrent infections, lymphoid hyperplasia
explanation: >-
Recurrent infection is the recognised clinical consequence of the
antibody-defense failure in UNG deficiency.
- name: Reduced Class-Switched Memory B Cells
biological_scale: CELLULAR
description: >-
B cells that cannot complete class switching fail to enter the
switched-memory compartment, while total B-cell numbers remain normal — a
feature distinguishing HIGM5 from the agammaglobulinemias.
cell_types:
- preferred_term: class switched memory B cell
term:
id: CL:0000972
label: class switched memory B cell
modifier: DECREASED
downstream:
- target: Decreased class-switched memory B cell proportion
description: >-
Switched-memory B cells are markedly reduced or absent in the circulating
repertoire.
evidence:
- reference: PMID:33276124
reference_title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSRD patients showed uniformly absent or markedly reduced switched
memory B cells (IgM-IgD-CD27+).
explanation: >-
Switched-memory B cells were absent or markedly reduced across the
class-switch recombination defect cohort, which included UNG-deficient
patients.
- name: Germinal Center and Lymphoid Hyperplasia
biological_scale: TISSUE
description: >-
Continued antigen-driven activation of B cells that cannot complete an
effective switching reaction drives enlargement of lymph nodes and
germinal centers, the lymphoid hyperplasia characteristic of the AID/UNG
hyper-IgM subgroup.
downstream:
- target: Lymphadenopathy
description: Enlarged lymph nodes and germinal centers.
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased | Enlarged lymph nodes and germinal centers"
explanation: The IUIS 2024 UNG deficiency row lists enlarged lymph nodes and germinal centers.
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
UNG-deficiency results in the hyper IgM syndrome characterized by
recurrent infections, lymphoid hyperplasia
explanation: >-
Lymphoid hyperplasia is a recognised feature of human UNG deficiency.
phenotypes:
- name: Increased circulating IgM level
category: Laboratory
description: >-
Serum IgM is normal or elevated, often markedly, because IgM-expressing B
cells cannot switch to downstream isotypes.
phenotype_term:
preferred_term: Increased circulating IgM level
term:
id: HP:0003496
label: Increased circulating IgM level
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased"
explanation: The IUIS 2024 UNG deficiency row records elevated IgM.
- name: Decreased circulating IgG concentration
category: Laboratory
description: Severe, persistent IgG deficiency is the central diagnostic abnormality.
phenotype_term:
preferred_term: Decreased circulating IgG concentration
term:
id: HP:0004315
label: Decreased circulating IgG concentration
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased"
explanation: The IUIS 2024 UNG deficiency row records decreased IgG.
- name: Decreased circulating IgA concentration
category: Laboratory
description: IgA is severely reduced or absent.
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNG deficiency | UNG | AR | 191525 | IgG and IgA decreased, IgM increased"
explanation: The IUIS 2024 UNG deficiency row records decreased IgA.
- name: Decreased circulating IgE concentration
category: Laboratory
description: >-
IgE is low or absent, as expected from failure to switch to the Cepsilon
constant region.
phenotype_term:
preferred_term: Decreased circulating IgE concentration
term:
id: HP:0005479
label: Decreased circulating IgE concentration
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "extremely low IgG, IgA and IgE and elevated IgM"
explanation: The review records low IgE as part of the UNG-deficiency serum profile.
- name: Impaired immunoglobulin class-switch recombination
category: Laboratory
description: >-
Patient B cells fail to generate normal switched isotypes despite
activation; in-vitro CSR is profoundly impaired.
phenotype_term:
preferred_term: Impaired immunoglobulin class-switch recombination
term:
id: HP:0002959
label: Impaired Ig class switch recombination
evidence:
- reference: PMID:12958596
reference_title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "profound impairment in CSR at a DNA precleavage step"
explanation: Patient cells show profound impairment of class-switch recombination.
- name: Impaired specific antibody response
category: Laboratory
description: >-
Antigen-specific IgG responses to vaccines and neoantigens are poor, with
failure of memory amplification and class switching on immunization.
phenotype_term:
preferred_term: Impaired specific antibody response
term:
id: HP:0012475
label: Impaired specific antibody response
evidence:
- reference: PMID:33276124
reference_title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Antibody response to phage was remarkably decreased with lack of memory
amplification and class-switching in immunized CD40L, UNG deficient, and
NEMO patients.
explanation: >-
UNG-deficient patients mounted a markedly decreased antibody response to a
neoantigen.
- name: Decreased class-switched memory B cell proportion
category: Laboratory
description: >-
Switched-memory B cells are markedly reduced or absent while total B-cell
numbers are normal.
phenotype_term:
preferred_term: Decreased class-switched memory B cell proportion
term:
id: HP:0030388
label: Decreased class-switched memory B cell proportion
evidence:
- reference: PMID:33276124
reference_title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CSRD patients showed uniformly absent or markedly reduced switched memory
B cells (IgM-IgD-CD27+).
explanation: >-
Class-switch recombination defects, including UNG deficiency, reduce
switched-memory B cells.
- name: Recurrent bacterial infections
category: Clinical
description: >-
Recurrent bacterial infection is the principal clinical burden. Published
HIGM5 reports describe it only in general terms; specific sites and
sequelae are not documented for this disease.
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
evidence:
- reference: PMID:17116429
reference_title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "UNG-deficiency results in the hyper IgM syndrome characterized by recurrent infections"
explanation: Recurrent infection is the recognised clinical feature of UNG deficiency.
- reference: PMID:15967827
reference_title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "including susceptibility to bacterial infections and lymphoid hyperplasia"
explanation: >-
Names bacterial infection specifically as part of the clinical picture of
UNG-deficient patients; framing sentence rather than the paper's own
experimental result.
- name: Lymphadenopathy
category: Clinical
description: >-
Chronic or recurrent lymph-node and germinal-center enlargement, a feature
of the AID/UNG hyper-IgM subgroup.
phenotype_term:
preferred_term: Lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: PMID:41608114
reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "Enlarged lymph nodes and germinal centers"
explanation: The IUIS 2024 UNG deficiency row records enlarged lymph nodes and germinal centers.
genetic:
- name: UNG
notes: >-
UNG (12q24.11) encodes uracil-DNA glycosylase, produced as a mitochondrial
isoform (UNG1) and a nuclear isoform (UNG2); UNG2 is the species required in
activated B cells. Biallelic loss-of-function variants cause HIGM5. Reported
alleles include truncating frameshift and nonsense variants yielding
catalytically dead or absent protein, and the F251S missense allele, whose
protein is enzymatically competent in bacteria but mistargeted to
mitochondria and degraded in mammalian B cells, leaving only trace nuclear
activity. No dominant-negative or gain-of-function mechanism is established.
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: UNG
term:
id: hgnc:12572
label: UNG
association: Causative
variants:
- name: UNG F251S
type: missense
description: >-
Homozygous Phe251Ser missense substitution in the UNG catalytic domain.
The purified enzyme is active and stable in vitro, but in mammalian cells
it is aberrantly sorted to mitochondria and degraded, so only ~0.4% of
normal nuclear uracil-excision activity remains — explaining the hyper-IgM
phenotype despite retained intrinsic catalytic capacity.
gene:
preferred_term: UNG
term:
id: hgnc:12572
label: UNG
evidence:
- reference: PMID:15967827
reference_title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
it was mistargeted to mitochondria and degraded in mammalian cells
explanation: >-
Characterizes the F251S allele as an expression/localization defect
rather than a loss of intrinsic catalytic activity.
evidence:
- reference: PMID:12958596
reference_title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
recessive mutations of the gene encoding uracil-DNA glycosylase (UNG) are
associated with profound impairment in CSR at a DNA precleavage step
explanation: >-
The gene-discovery study identifying recessive UNG mutations as the cause
of HIGM5.
diagnosis:
- name: Serum immunoglobulin quantitation and class-switch evaluation
description: >-
Diagnosis rests on the serum profile (normal/elevated IgM with low IgG and
IgA), normal total B-cell numbers with reduced class-switched memory B
cells, poor specific antibody responses, and biallelic UNG variants, after
excluding the more common CD40L form by CD40L expression/binding assays.
notes: >-
No HIGM5-specific diagnostic criteria exist; evaluation follows the general
hyper-IgM/CSR-deficiency work-up. Molecular confirmation uses a hyper-IgM /
primary-antibody-deficiency gene panel including CD40LG, CD40, AICDA and UNG.
treatments:
- name: Immunoglobulin Replacement Therapy
description: >-
Regular intravenous or subcutaneous IgG replacement is the mainstay,
supplying the switched antibody patients cannot make and reducing infection
frequency. It does not correct the underlying enzymatic defect.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: immunoglobulin replacement therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
therapeutic_agent:
- preferred_term: human immunoglobulin G
term:
id: NCIT:C80829
label: Human Immunoglobulin G
target_mechanisms:
- target: Defective Opsonizing and Mucosal Antibody Defense
treatment_effect: BYPASSES
description: >-
Passive IgG supplies the opsonizing antibody the patient cannot generate,
bypassing rather than repairing the class-switch block.
notes: >-
No HIGM5-specific controlled trial exists; immunoglobulin replacement
follows general primary-antibody-deficiency practice, so no evidence item is
attached rather than citing a source that does not address HIGM5.
- name: Antibiotic Therapy and Prophylaxis
description: >-
Antibiotics treat the recurrent bacterial infections, and prophylactic
regimens may be added alongside immunoglobulin replacement when infection
continues.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
target_mechanisms:
- target: Defective Opsonizing and Mucosal Antibody Defense
treatment_effect: INHIBITS
description: >-
Antibiotics eradicate or suppress the bacterial infections the missing
switched antibody cannot prevent or clear.
notes: >-
No HIGM5-specific antibiotic trial exists; use follows general
primary-antibody-deficiency practice, so no evidence item is attached.
differential_diagnoses:
- name: Hyper-IgM syndrome type 2 (AID deficiency)
description: >-
AID (AICDA) deficiency is the closest phenocopy — the same B-cell-intrinsic
CSR block, the same lymphoid hyperplasia, and the same bacterial
susceptibility — because UNG acts immediately downstream of AID in the same
pathway. Somatic hypermutation is generally more severely reduced or absent
in AID deficiency, whereas UNG deficiency distorts the SHM spectrum rather
than abolishing it. The two are separated by the causal gene.
disease_term:
preferred_term: hyper-IgM syndrome type 2
term:
id: MONDO:0011528
label: hyper-IgM syndrome type 2
distinguishing_features:
- Biallelic AICDA versus biallelic UNG variants.
- SHM typically absent/severely reduced in AID deficiency, distorted (spectrum shift) in UNG deficiency.
evidence:
- reference: PMID:15661022
reference_title: "Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
the observation that uracil-DNA-glycosylase deficiency leads to a severe
hyper-IgM syndrome strongly argues in favor of a DNA-editing activity of AID
explanation: >-
Places UNG deficiency in the same AID-dependent CSR pathway as AID
deficiency, the basis for their close resemblance.
- name: Hyper-IgM syndrome type 1 (CD40 ligand deficiency)
description: >-
The X-linked CD40LG defect produces the same serum pattern but, because it
additionally loses T-cell licensing of macrophages and dendritic cells,
carries opportunistic and fungal infection, neutropenia and sclerosing
cholangitis — none characteristic of the B-cell-intrinsic UNG defect.
disease_term:
preferred_term: hyper-IgM syndrome type 1
term:
id: MONDO:0010626
label: hyper-IgM syndrome type 1
distinguishing_features:
- X-linked (males) versus autosomal recessive.
- Opportunistic infection, neutropenia and sclerosing cholangitis point to CD40L deficiency, not UNG deficiency.
evidence:
- reference: PMID:15358621
reference_title: "Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1
female); UNG in one adult male; and Btk in 3 boys.
explanation: >-
In a molecular hyper-IgM cohort CD40L deficiency dominates and UNG
deficiency is rare, the clinical prior that drives the work-up order.
- name: Hyper-IgM syndrome type 3 (CD40 deficiency)
description: >-
Biallelic CD40 loss is the autosomal recessive phenocopy of CD40L
deficiency and shares its combined-immunodeficiency, opportunistic-infection
profile, which separates it from the antibody-only UNG defect.
disease_term:
preferred_term: hyper-IgM syndrome type 3
term:
id: MONDO:0011735
label: hyper-IgM syndrome type 3
distinguishing_features:
- Autosomal recessive like UNG deficiency, but with the opportunistic infections of a CD40-axis defect.
- IUIS places CD40 deficiency in Table 1 (combined immunodeficiency) rather than among the predominantly antibody deficiencies.
progression:
- phase: Onset and course
age_range: Biological onset congenital; clinical onset variable, infancy to adolescence
notes: >-
Biallelic variants are present from conception, but clinical onset is
variable and HIGM5 may present later than CD40L deficiency. The course is a
chronic lifelong immunodeficiency with episodic bacterial infection
superimposed on persistent immunoglobulin abnormalities. Long-term
complications such as chronic airway damage are expected from other
antibody deficiencies but have not been documented in published HIGM5
patients. No validated staging system exists, and spontaneous remission is
not expected.
clinical_burden:
burden_level: MODERATE
rationale: >-
The infectious burden is largely correctable by immunoglobulin replacement,
and because T-cell and myeloid function are preserved there is no
opportunistic-infection or sclerosing-cholangitis mortality driver as in the
CD40-axis forms. Residual burden comes from recurrent bacterial infection,
lymphoid hyperplasia, and the lifelong demand of replacement therapy and
monitoring. HIGM5-specific survival data do not
exist; prognosis is considered better than in the CD40/CD40L disorders.
animal_models:
- name: Ung-knockout mouse
species: Mouse
genotype: Ung(-/-) null
publication: PMID:12401169
description: >-
Gene-targeted Ung-null mice reproduce the mechanism but not the full human
severity: class-switch recombination is only partly inhibited (a
mismatch-repair backup operates in mice), and somatic hypermutation at G:C
pairs is shifted strongly toward transitions. Aged Ung-null mice develop
B-cell lymphomas, a finding specific to the mouse that should not be read as
a demonstrated human cancer risk.
modeled_mechanisms:
- target: Altered Somatic Hypermutation Spectrum
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
description: >-
Ung-null mice reproduce the directional skew of the SHM spectrum (excess
G:C transitions, reduced transversions).
limitations: >-
Mouse class-switch recombination is only partly inhibited, unlike the
profound human block, because a mismatch-repair backup operates in mice;
so the model understates the human CSR defect.
readouts:
- name: G:C transition fraction during somatic hypermutation
target: Altered Somatic Hypermutation Spectrum
direction: INCREASED
interpretation: >-
Loss of abasic-site formation shifts G:C-pair mutations toward
transitions, the structural correlate of the SHM-spectrum node.
evidence:
- reference: PMID:12401169
reference_title: "Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mutations at dC/dG pairs are dramatically shifted toward transitions
(95%)
explanation: Quantifies the transition-biased SHM spectrum in the model.
- target: Impaired Class-Switch Recombination
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Switching is inhibited in Ung-null mice but not abolished, so the model
only partly recapitulates the profound human CSR block.
limitations: >-
A mismatch-repair backup leaves murine CSR substantially but not totally
inhibited, whereas human UNG deficiency produces a profound precleavage
block; the model therefore underrepresents the human phenotype's severity.
evidence:
- reference: PMID:12401169
reference_title: "Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Class-switch recombination is substantially, but not totally, inhibited.
explanation: >-
Documents the partial, not complete, CSR inhibition that distinguishes
the mouse from the human disease.
evidence:
- reference: PMID:12934097
reference_title: "Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a greatly increased incidence of B-cell lymphomas in older Ung-deficient mice
explanation: >-
A second Ung-null mouse line develops B-cell lymphomas with age; recorded
here as a model-organism finding only, not a demonstrated human cancer risk.
discussions:
- discussion_id: higm5_cancer_risk_only_model_organism
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#Failure of Switch-Region Uracil Excision
prompt: >-
Does the elevated genomic uracil and lymphomagenesis seen in aged
Ung-knockout mice translate into an increased malignancy risk in human UNG
deficiency?
rationale: >-
Aged Ung-null mice develop B-cell lymphomas, and patient B-cell lines
accumulate genomic uracil, so a lymphoma risk is mechanistically plausible.
But the lymphoma phenotype is demonstrated only in the mouse, the human
cohort is tiny, and no quantitative human HIGM5 cancer incidence has been
established. Whether the mouse finding reflects human risk or a
species-specific consequence of chronic genomic-uracil load is unresolved.
proposed_experiments:
- experiment_id: higm5_malignancy_surveillance
name: Long-term malignancy surveillance of molecularly confirmed UNG-deficient patients
description: >-
Pooled longitudinal follow-up of the small confirmed HIGM5 cohort to
estimate lymphoma/malignancy incidence against age-matched expectation.
- discussion_id: higm5_population_prevalence_unknown
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- prevalence#Worldwide
prompt: >-
What is the true population prevalence and carrier frequency of UNG
deficiency?
rationale: >-
Every reported figure is a referral-based case count; Orphanet lists
prevalence as unavailable and the F251S allele is extremely rare in
population databases. Because the disease is autosomal recessive and the
infectious phenotype is milder than CD40L deficiency, under-ascertainment is
plausible, but no denominator-based study has been done.
references:
- reference: PMID:12958596
title: "Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination."
- reference: PMID:15967827
title: "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil."
- reference: PMID:38000394
title: "RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork."
- reference: PMID:31507588
title: "Repertoire Sequencing of B Cells Elucidates the Role of UNG and Mismatch Repair Proteins in Somatic Hypermutation in Humans."
- reference: PMID:12401169
title: "Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice."
- reference: PMID:12934097
title: "Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas."
- reference: PMID:17116429
title: "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity."
- reference: PMID:33276124
title: "Class Switch Recombination Defects: impact on B cell maturation and antibody responses."
- reference: PMID:15358621
title: "Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome."
- reference: PMID:15661022
title: "Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects."
- reference: PMID:17560278
title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
- reference: PMID:41608114
title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
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.
Create: Hyper-IgM Syndrome Type 5 · 2026-10-18T05:34:52Z · View source
De-novo curation of HIGM5 (UNG deficiency, MONDO:0011971, gene UNG hgnc:12572) from Perplexity deep research (preflight-dr PASS). UNG-loss pathophysiology chain from failed switch-region uracil excision to CSR failure, altered SHM spectrum, hyper-IgM serum profile, recurrent sinopulmonary infection and lymphoid hyperplasia; phenotypes wired to the graph; UNG gene wired via a genes descriptor on the lesion node. IUIS 2024 Table 3 classification (PMID:41608114) and a member row added to the Predominantly Antibody Deficiencies IEIs grouping mirroring HIGM2. 38 exact-quote snippets over 12 distinct PMIDs verified against the reference cache. Ung-knockout mouse recorded as MODEL_ORGANISM (partial CSR block, SHM transition bias, late B-cell lymphomas) with a HUMAN_MODEL_MISMATCH discussion on human cancer risk. Excluded the Yilmaz 2022 Research Square preprint (VUS, unreviewed) and the two report references flagged unresolved/off-topic. No GeneReviews chapter exists (offline + online check). Validated with validate-disorders, validate-terms, count-verified-snippets (38/38), entity-refs, causal-targets, duplicate-keys, qualifier-terms, and the whole-KB snippet/title/grading/retired-prose/coarse-phenotype/reference-title/block-scalar checks.
Disease: Hyper-IgM syndrome type 5
Preferred molecular name: UNG-related immunodeficiency / hyper-IgM syndrome due to uracil-DNA glycosylase deficiency
MONDO: MONDO:0011971
Category: Mendelian, predominantly antibody deficiency
Report date: October 18, 2026
Hyper-IgM syndrome type 5 (HIGM5) is an extremely rare autosomal-recessive, B-cell-intrinsic immunodeficiency caused by biallelic loss-of-function variants in UNG. UNG normally removes activation-induced cytidine deaminase (AID)-generated uracil from immunoglobulin DNA. Its absence profoundly impairs immunoglobulin class-switch recombination (CSR), leaving affected people with normal or elevated IgM but markedly reduced IgG and IgA, deficient class-switched memory B cells, poor specific antibody responses, recurrent bacterial—especially sinopulmonary—infections, and lymphoid hyperplasia. T-cell immunity and total B-cell numbers are usually preserved, so opportunistic infection and neutropenia are not characteristic, unlike CD40/CD40L-pathway hyper-IgM disorders. [2][193][445]
The evidence base is unusually small. The landmark report described three patients (PMID: 12958596), a large 140-patient hyper-IgM cohort found only one UNG-deficient individual (0.7%; PMID: 15358621), and a 2022 report added a 40-year-old patient with a novel biallelic insertion (PMID: 35879489). Thus, phenotype frequencies, penetrance, survival and treatment-response percentages cannot be estimated reliably. [31][449][148]
HIGM5 is a primary immunodeficiency in which impaired UNG-mediated processing of uracil in activated B-cell immunoglobulin loci causes a severe CSR defect. Immunologically, the defining pattern is:
The 2024 IUIS classification places UNG deficiency under “predominantly antibody deficiencies,” specifically “severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells.” [193][199]
| Resource | Identifier/name |
|---|---|
| MONDO | MONDO:0011971, hyper-IgM syndrome type 5 |
| OMIM disease | 608106, Immunodeficiency with hyper-IgM, type 5 |
| OMIM gene | 191525, UNG |
| Orphanet | ORPHA:101092 |
| Disease Ontology | DOID:0060759 |
| MeSH | D053306, Hyper-IgM Immunodeficiency Syndrome |
| ICD-10 | D80.5, Immunodeficiency with increased immunoglobulin M |
| ICD-11 | 4A01.05, Immunodeficiency with hyper-IgM; Orphanet also maps the non-opportunistic HIGM grouping to 4A01.1Y |
| SNOMED CT | 1351569004, autosomal-recessive hyperimmunoglobulin M syndrome due to UNG deficiency |
| MedGen/UMLS | C1720958 |
| GARD | 10581 |
| HGNC gene | HGNC:12572, UNG |
| NCBI Gene | 7374 |
| Ensembl | ENSG00000076248 |
| UniProt | P13051 |
The ICD and MeSH terms are umbrella HIGM codes rather than HIGM5-specific billing codes. [1][3][118][418][419][423]
Common synonyms
This report concerns an aggregated disease entity, not an EHR-derived phenotype. The strongest evidence comes from:
Ung-knockout mice and engineered B-cell lines;The established cause is biallelic germline pathogenic variants in UNG, producing absent, unstable, mistargeted or catalytically nonfunctional uracil-DNA glycosylase. Homozygous and compound-heterozygous genotypes have been documented. No infectious, toxic, nutritional or lifestyle exposure causes HIGM5. [2][31]
UNG is located at 12q24.11 and produces two principal isoforms through alternative promoter use and splicing:
NCBI Gene assigns UNG Gene ID 7374, HGNC 12572 and Ensembl ENSG00000076248. [118][121]
| Risk factor | Evidence and interpretation |
|---|---|
Two pathogenic UNG alleles in trans |
Necessary and sufficient cause under the established autosomal-recessive model |
| Consanguinity | Increases the probability that both parents carry the same rare allele; the 39-year-old cohort patient’s parents were first cousins [97] |
| Affected sibling/family history | Each sibling of an affected individual has a 25% recurrence risk when both parents are heterozygous carriers |
| Rare loss-of-function alleles | Frameshift, nonsense and damaging missense alleles have been reported |
| Population-specific alleles | Possible, but no replicated founder mutation has been established |
| Sex | Both sexes are genetically susceptible; unlike CD40LG deficiency, HIGM5 is not X-linked |
Environment does not initiate the genetic disorder, but exposure to encapsulated respiratory bacteria determines when and how severely antibody failure becomes clinically evident. Crowding, daycare, smoke exposure, chronic airway disease and delayed access to immunoglobulin replacement are plausible severity modifiers, but none has been formally quantified in HIGM5.
The principal reported infections are upper and lower respiratory bacterial infections. Opportunistic infection is generally not increased because T-cell and myeloid CD40 signaling remain intact. [75][113][421]
No protective UNG allele has been established. Clinically protective measures include:
Residual activity or compensation by SMUG1 might moderate severity, but this is chiefly model-organism evidence. Human patient B-cell lines showed that SMUG1 could not compensate effectively for UNG loss. [116][448]
The genotype creates deficient switched-antibody production; pathogen exposure then reveals the phenotype. Maternal IgG may temporarily protect infants, while recurrent respiratory exposure progressively produces airway injury. This is not a classic toxicogenomic interaction and no formal HIGM5 G×E study has been published.
Because only a handful of molecularly confirmed patients have been described, valid percentages are unavailable. Frequencies below are therefore qualitative.
| Phenotype and type | Typical characteristics | Suggested HPO term |
|---|---|---|
| Hyper-IgM laboratory phenotype | Normal/elevated IgM; persistent; often marked | HP:0003496, Increased circulating IgM |
| Low IgG | Severe, persistent; central diagnostic abnormality | HP:0004315, Decreased circulating IgG |
| Low/absent IgA | Severe, persistent | HP:0002720, Decreased circulating IgA |
| Low IgE | Expected from CSR failure; incompletely reported in individual cases | HP:0003212, Decreased circulating IgE |
| Impaired class-switch recombination | Severe; patient B cells fail to generate normal IgG/IgA despite activation | HP:0002959, Impaired immunoglobulin class-switch recombination |
| Reduced class-switched memory B cells | Marked or absent; one repertoire-study patient had 0.7% versus a reference range of 6.5–29.1% | HP:0032137, Decreased class-switched memory B cells |
| Poor vaccine-specific antibody response | Persistent; abnormal pneumococcal antibody response documented | HP:0032126, Abnormality of specific antibody response |
| Recurrent bacterial infections | Usually childhood or adolescent onset; episodic; variable severity | HP:0002718, Recurrent bacterial infections |
| Recurrent upper/lower respiratory infection | Sinusitis, otitis, bronchitis or pneumonia; major morbidity | HP:0200117, Recurrent upper and lower respiratory tract infections |
| Lymphadenopathy | Chronic or recurrent lymphoid hyperplasia; common in the AID/UNG HIGM subgroup | HP:0002716, Lymphadenopathy |
| Splenomegaly | Reported as part of the autosomal-recessive HIGM lymphoid-hyperplasia phenotype; exact HIGM5 frequency unknown | HP:0001744, Splenomegaly |
| Tonsillar/adenoidal hypertrophy | May produce snoring or obstructive symptoms; subgroup-level evidence | HP:0030817, Tonsillar hypertrophy |
| Pulmonary lymphoid hyperplasia | Documented in one adult UNG-deficient patient and progressive despite IVIG | HP:0006535, Abnormal pulmonary interstitial morphology / use a more specific local term if available |
| Epididymitis | Documented in one adult patient; very rare | HP:0000031, Epididymitis |
| Sjögren syndrome/autoimmunity | Documented in one adult; autoimmune disease is considered a possible AID/UNG feature | HP:0002814, Abnormality of the immune system; annotate Sjögren syndrome separately |
| Normal total B-cell count | Distinguishes HIGM5 from agammaglobulinemias | HP:0002845, Normal B-cell count, if supported by local ontology |
| Absence of neutropenia | Negative distinguishing feature rather than phenotype | Do not encode as a positive HPO phenotype |
| No characteristic behavioral phenotype | No consistent neurobehavioral manifestation reported | Not applicable |
The landmark cases had bacterial susceptibility, lymphoid hyperplasia, elevated IgM and profoundly decreased IgG/IgA. [61] The best-described adult became symptomatic at 15 years and had IgM 785 mg/dL, IgG 209 mg/dL, IgA <6.7–7 mg/dL, abnormal pneumococcal responses, chronic epididymitis, Sjögren syndrome and pulmonary lymphoid hyperplasia. [442]
No HIGM5-specific EQ-5D, SF-36 or PROMIS study exists. Expected burdens include recurrent illness and hospitalization, chronic airway symptoms, fatigue, missed education/work, regular IVIG/SCIG administration and anxiety concerning infection and hereditary risk. Home SCIG may reduce travel and scheduling burden, but comparative HIGM5 quality-of-life data are unavailable.
| Field | Value |
|---|---|
| Symbol | UNG |
| Full name | Uracil DNA glycosylase |
| HGNC | HGNC:12572 |
| NCBI Gene | 7374 |
| OMIM | 191525 |
| Ensembl | ENSG00000076248 |
| UniProt | P13051 |
| Chromosome | 12q24.11 |
| Inheritance | Autosomal recessive |
| Molecular consequence | Loss of nuclear UNG activity, usually loss of function |
The transcript used by modern ClinVar records is frequently NM_080911.3; older publications used different numbering, so legacy and current descriptions should not be mixed without transcript normalization.
| Variant | Type/genotype | Classification/evidence | Functional consequence |
|---|---|---|---|
| NM_080911.3:c.392del; p.Pro131HisfsTer13; legacy “462delC” | Frameshift; reported in compound heterozygosity and later as homozygous in a repertoire-study patient | ClinVar pathogenic, Variation ID 12290; PMID 12958596 | Premature termination; absent/disrupted protein |
| NM_080911.3:c.572_573del; p.Glu191fs; legacy “639delTA” | Frameshift, compound-heterozygous partner | ClinVar pathogenic, Variation ID 12291 | Truncation, catalytic-domain loss |
| NM_080911.3:c.752T>C; p.Phe251Ser, rs104894380 | Homozygous missense | ClinVar pathogenic, Variation ID 12292 | Catalytically active in bacteria but poorly expressed, mistargeted toward mitochondria and degraded in mammalian cells |
| NM_080911.3:c.428_429del; p.Ile143fs; legacy “497_498delAT” | Homozygous frameshift | ClinVar pathogenic, Variation ID 12293 | Premature termination around residue 159 |
| c.924_925insGG, transcript as reported | Homozygous insertion | Novel in a 40-year-old patient; PMID 35879489 | Predicted frameshift/loss of function; transcript normalization and independent replication needed |
| c.685C>T; p.Arg229Ter, rs772214871 | Nonsense | ClinVar pathogenic, Variation ID 578381 | Predicted nonsense-mediated decay or truncated protein |
| c.730C>T; p.Gln244Ter, rs751126274 | Nonsense | ClinVar pathogenic submission | Predicted loss of function |
| c.371A>G; p.His124Arg | Missense | ClinVar VUS | Insufficient evidence; not diagnostic by itself |
| c.*537G>A | 3′ UTR | ClinVar VUS | No published disease evidence |
The two original truncating variants and F251S all affected the catalytic domain; protein was absent from patient B-cell lines, indicating instability or degradation. [46][47][61][116]
The F251S allele is exceptionally rare: gnomAD v4 exomes reported 4/595,596 alleles, global allele frequency about 7×10⁻⁶, with no evidence of homozygotes in the cited summary. [253]
Important curation caution: ClinVar contains many UNG submissions attached to the disease record, including benign and uncertain variants. Only biallelic variants with appropriate segregation, rarity and functional/clinical evidence should be considered causal.
UNG are theoretically detectable but are not a recognized common mechanism.No human modifier gene has been validated. Candidate compensatory or interacting factors include:
SMUG1, a backup uracil glycosylase;MSH2/MSH6, mismatch-repair pathway;APE1/APEX1 and APEX2, AP-site processing;RPA1/RPA2/RPA3, recruitment to single-stranded DNA;PCNA, replication-associated recruitment;POLH, error-prone synthesis;FAM72A, which regulates UNG2 abundance during antibody diversification.These are mechanistic candidates, not clinically validated severity modifiers.
No reproducible HIGM5-specific DNA-methylation, histone-mark, chromatin or episignature has been reported.
| Domain | Current evidence |
|---|---|
| Toxins, radiation, pollution | No evidence that they cause HIGM5 |
| Smoking/air pollution | Plausibly aggravate respiratory morbidity but not studied specifically |
| Diet, alcohol, exercise | No demonstrated effect on disease occurrence |
| Occupational exposure | No established association |
| Infectious agents | Primarily bacterial respiratory pathogens act as complications, not causes |
| Opportunistic pathogens | Not characteristically increased in isolated UNG deficiency |
| Gene–environment studies | None specific to HIGM5 |
Encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae are biologically expected in severe antibody deficiency, although organism-level frequencies have not been published for HIGM5.
UNG variants lead to absent, unstable, mistargeted or nonfunctional nuclear UNG protein in activated B cells. Cμ to Cγ, Cα or Cε. AID converts cytosine to uracil at transcribed immunoglobulin switch and variable regions. UNG normally hydrolyzes the uracil–deoxyribose N-glycosidic bond, producing an AP site. AP endonucleases and mismatch-repair proteins then create and process DNA breaks. Nonhomologous end joining joins the donor Sμ region to a downstream switch region, replacing the constant region while retaining antigen specificity.
The original human study summarized the central finding:
“Recessive mutations of the gene encoding uracil–DNA glycosylase (UNG) are associated with profound impairment in CSR at a DNA precleavage step and with a partial disturbance of the SHM pattern in three patients with hyper-IgM syndrome.”
— Imai et al., Nature Immunology, published September 7, 2003; PMID 12958596, DOI 10.1038/ni974. [31][58]
Patient B-cell studies showed:
99% of normal high-turnover ssDNA uracil-excision activity is attributable to UNG;
The 2005 study’s abstract states:
“In B cell lines from hyper-IgM patients carrying UNG mutations, the single-strand-specific uracil-DNA glycosylase, SMUG1, cannot complement this function. Moreover, the UNG mutations lead to increased accumulation of genomic uracil.”
— Kavli et al., Journal of Experimental Medicine, June 20, 2005; PMID 15967827, DOI 10.1084/jem.20050042. [448]
UNG deficiency does not simply abolish all SHM. It changes the mutation spectrum:
Human BCR repertoire sequencing found approximately:
That study included only one UNG-deficient patient, so the estimates should not be interpreted as population frequencies. [508]
A major recent development was demonstration that UNG1 and UNG2 contain an RPA-binding helix that permits access to RPA-coated ssDNA. CRISPR-engineered CH12F3 B cells carrying UNG RPA-binding mutations had approximately 80% lower IgA switching after stimulation; in an appropriate UNG2-knockout context, RPA-binding-deficient UNG1 produced complete switching failure. Total genomic uracil was not comparably increased, indicating mechanistic separation between RPA-dependent antibody-locus processing and canonical dsDNA BER. [316][319]
“We show that the UNG:RPA interaction plays a crucial role in both CSR and repair of AID-induced uracil at the Ig loci.”
— Hayran et al., Nucleic Acids Research, January 25, 2024; PMID 38000394, DOI 10.1093/nar/gkad1115. [463]
This refines the classical model: HIGM5 is not merely failure of generic DNA repair; it is failure of specialized recruitment and processing of AID-created uracil at activated B-cell immunoglobulin loci.
GO biological process/molecular function
Cell Ontology
GO cellular component
The key pathway is Reactome R-HSA-73884, Base Excision Repair, particularly AP-site formation. [121][368][373][377][478]
| Modality | Disease-specific evidence |
|---|---|
| BCR repertoire sequencing | Available; one UNG-deficient patient, confirming altered SHM spectra [508] |
| Bulk transcriptomics | No replicated HIGM5-specific expression signature |
| Proteomics | No clinical HIGM5 proteomic biomarker |
| Metabolomics/lipidomics | None established |
| Single-cell RNA sequencing | No disease-specific patient study identified |
| Spatial transcriptomics | None |
| Multi-omics | None |
| CRISPR functional genomics | CH12F3 UNG isoform and RPA-binding studies available [314][316] |
| Patient iPSC/organoid models | None established |
| Level | Structure/cell/compartment | Role |
|---|---|---|
| System | Immune and lymphatic system — UBERON:0002405 | Primary disease system |
| Organ | Lymph node — UBERON:0000029 | Germinal-center B-cell activation; lymphadenopathy |
| Organ | Spleen — UBERON:0002106 | Secondary lymphoid activation; possible splenomegaly |
| Organ | Tonsil/adenoid | Lymphoid hypertrophy; airway obstruction possible |
| Tissue | Bone marrow — UBERON:0002371 | B-cell origin; not the principal site of the CSR lesion |
| Organ | Lung | Recurrent infection, possible bronchiectasis and pulmonary lymphoid hyperplasia |
| Organ | Paranasal sinuses/middle ear | Recurrent bacterial disease |
| Organ | Epididymis | Epididymitis in one patient |
| Cell | Germinal-center/activated B cell — CL:0000844 | Principal functionally affected cell |
| Cell | Class-switched memory B cell | Markedly reduced output |
| Subcellular | Nucleus/nucleoplasm | UNG2-mediated immunoglobulin-locus processing |
| Subcellular | Mitochondrion | UNG1; F251S mutant mistargeting reported |
| Molecular locus | Immunoglobulin heavy-chain switch and variable regions | CSR and SHM substrate |
No consistent lateralization exists. Respiratory and lymphoid involvement is systemic or bilateral rather than unilateral.
No validated disease-stage or staging system exists.
| Feature | Assessment |
|---|---|
| Mode | Autosomal recessive |
| Risk to siblings when both parents are carriers | 25% affected, 50% carrier, 25% neither per pregnancy |
| Sex ratio | Expected 1:1 |
| Penetrance | Not numerically established; likely high for severe biallelic loss-of-function genotypes |
| Expressivity | Variable, including childhood versus adolescent/adult onset |
| Anticipation | Not expected |
| Germline mosaicism | Theoretically possible but not reported |
| Consanguinity | Relevant; documented in at least one patient |
| Founder effects | None securely established |
| Carrier phenotype | Heterozygotes are generally expected to be asymptomatic |
| Carrier frequency | Unknown |
No reliable HIGM5 incidence or prevalence estimate exists; Orphanet lists prevalence as unavailable. [245]
Useful context, not a HIGM5 prevalence estimate:
No ethnicity, geography or demographic group has a demonstrated increased HIGM5 prevalence. Apparent regional clustering is likely to reflect consanguinity, founder alleles or ascertainment.
CD40LG, CD40, AICDA and UNG.Normal CD40L staining does not fully exclude CD40LG dysfunction; ligand-binding assays and sequencing remain important. Patients with normal CD40L expression/binding should be assessed for autosomal-recessive CD40, AICDA and UNG disease. [408]
| Test | Expected HIGM5 result |
|---|---|
| Serum IgM | Normal or elevated, sometimes markedly |
| Serum IgG | Very low or absent |
| Serum IgA | Very low or absent |
| Serum IgE | Low/absent |
| Total B cells | Usually normal |
| Class-switched memory B cells | Markedly reduced or absent |
| Pneumococcal-specific IgG | Poor |
| T-cell counts/function | Usually preserved |
| Neutrophils | Usually normal |
| In-vitro CSR | Profoundly impaired |
| SHM | Frequency variably reduced; G:C transition bias and reduced transversions |
| UNG protein/activity | Absent or severely reduced in patient B-cell lines |
| Genomic uracil | Elevated in experimental patient B-cell assays |
Routine imaging is not diagnostic, but high-resolution chest CT is indicated for recurrent pneumonia, chronic cough or abnormal pulmonary function to assess bronchiectasis or lymphoid disease.
| Modality | Utility |
|---|---|
Single-gene UNG sequencing |
Appropriate when phenotype/functional evidence is strongly specific or familial variants are known |
| Multigene HIGM/PAD panel | Preferred first-line molecular test |
| WES | Useful when the panel is negative or phenotype is atypical |
| WGS | Can detect coding, noncoding and structural variants missed by WES; no proven superior HIGM5 diagnostic yield because cases are so rare |
| Deletion/duplication analysis | Add if sequencing finds one allele or suggests a copy-number event |
| CMA | Low yield for isolated HIGM5; not first-line |
| Karyotype/FISH | Not routinely indicated |
| mtDNA testing | Not indicated; UNG is nuclear encoded |
| Repeat-expansion testing | Not indicated |
| RNA sequencing | Research/adjunct for suspected splice variants |
| Functional UNG/CSR assay | Specialized research or reference-laboratory confirmation |
GTR lists clinical tests for HIGM5/UNG, but assay availability varies geographically. [500]
| Disorder | Distinguishing features |
|---|---|
| CD40LG deficiency/HIGM1 | X-linked; males; opportunistic infection, neutropenia, cryptosporidial liver disease; abnormal CD40L expression/function |
AICDA deficiency/HIGM2 |
Very similar lymphoid hyperplasia and bacterial disease; SHM generally more severely reduced/absent; biallelic AICDA variants |
CD40 deficiency/HIGM3 |
Combined immune defect with opportunistic infection |
NEMO/IKBKG deficiency |
Ectodermal dysplasia, infections and broader NF-κB dysfunction |
| PMS2/MSH6/MSH2 defects | CSR/SHM defects plus constitutional mismatch-repair deficiency and cancer predisposition |
| Common variable immunodeficiency | Low IgG/IgA, but IgM often low or normal; heterogeneous genetics; usually less specific CSR pattern |
| X-linked agammaglobulinemia | Very low/absent B cells rather than normal B-cell numbers |
| Secondary hypogammaglobulinemia | Medication, protein loss, malignancy or infection history; no biallelic UNG defect |
| Transient hypogammaglobulinemia of infancy | Spontaneous improvement and usually not persistent hyper-IgM |
| Ataxia-telangiectasia/Nijmegen breakage syndrome | Neurologic/syndromic features, radiosensitivity and characteristic laboratory findings |
There is no population newborn screen for HIGM5. TREC-based SCID screening is expected to be normal because T-cell development is preserved. Family-based molecular testing is therefore the principal presymptomatic strategy. [389]
No valid five-year survival, ten-year survival, mortality rate or median life expectancy has been calculated for HIGM5. Broad HIGM survival data are dominated by CD40LG deficiency and should not be transferred directly to UNG deficiency.
Prognosis in isolated AID/UNG antibody-switching defects is considered better than in CD40/CD40L disorders because T-cell immunity is preserved. With adequate Ig replacement and infection treatment, patients may live productive adult lives. [166][213]
The best-described adult had fewer infections after IVIG, but Sjögren syndrome and pulmonary lymphoid hyperplasia continued to progress. [442]
Likely favorable:
Likely adverse:
No validated prognostic biomarker or calculator exists.
| Intervention | Use and evidence | Major adverse effects/limitations | Suggested NCIt annotation |
|---|---|---|---|
| IVIG | Mainstay; typically initial total dose around 0.4–0.6 g/kg/month, individualized by infection burden and trough IgG | Infusion reaction, headache, thrombosis, hemolysis, renal injury, aseptic meningitis | Intravenous Immunoglobulin Therapy |
| SCIG | Equivalent replacement route; weekly or individualized schedules; supports home treatment | Local swelling/pain; frequent administration | Subcutaneous Immunoglobulin Therapy |
| Acute antibiotics | Culture-directed treatment of bacterial respiratory or other infections | Drug-specific toxicity/resistance | Antibiotic Therapy |
| Prophylactic antibiotics | Consider if infections persist despite adequate Ig; azithromycin, amoxicillin or TMP-SMX may be used depending on context | Resistance, allergy, gastrointestinal effects, QT risk for macrolides | Antibiotic Prophylaxis |
| Airway clearance/physiotherapy | For bronchiectasis or chronic secretion burden | Limited HIGM5-specific trial evidence | Respiratory Therapy |
| Autoimmune-disease therapy | Corticosteroids or other immunomodulators tailored to manifestation | Additional infection risk | Immunosuppressive Therapy |
| HSCT | Not routinely recommended for AID/UNG deficiency because the defect is confined largely to antibody production and manageable with Ig replacement | Conditioning toxicity, infection, GVHD, infertility, mortality | Hematopoietic Stem Cell Transplantation |
| Gene/RNA therapy | No approved or HIGM5-specific clinical program | Experimental | Gene Therapy / RNA Therapy |
| Genetic counseling | Recurrence-risk assessment and reproductive options | None intrinsic | Genetic Counseling |
Guidelines for primary antibody deficiency recommend individualized IgRT, commonly beginning around 0.4–0.6 g/kg/month; a trough above approximately 7 g/L is often used as an initial target but clinical infection control is more important than a universal numerical threshold. [230] HIGM guidance specifically identifies Ig replacement as necessary across HIGM forms. [166]
Generic HIGM references sometimes recommend HSCT because they are focused on CD40LG/CD40 deficiency. For isolated AID or UNG deficiency, expert patient guidance states that HSCT is not currently recommended because T-cell function is intact and antibody failure can generally be treated with Ig replacement. [166][170]
Disease-specific controlled trials do not exist. In the adult cohort patient:
No HIGM5-specific response percentage, comparative IVIG-versus-SCIG trial or pharmacogenomic predictor has been reported.
No interventional gene, cell, RNA or targeted therapy trial specific to HIGM5 was identified. The relevant current registry study is:
| Study | Type/status | Relevance |
|---|---|---|
| NCT06092346 — Prospective Study of the Clinical, Genomic, Pharmacological, Laboratory, and Dietary Determinants of Pyrimidine and Purine Metabolism Disorders | Observational natural-history study; started December 19, 2023 | Includes UNG/HIGM5 among eligible disorders; not a therapeutic trial [495] |
The disease cannot be prevented by lifestyle modification. Reproductive prevention options after familial-variant identification include:
Because HIGM5 preserves T-cell function, vaccine safety should be individualized rather than inferred from combined immunodeficiencies. Nevertheless:
CDC guidance lists OPV, smallpox, LAIV, BCG, live oral typhoid, yellow fever, MMR/MMRV and dengue live vaccine among contraindications for severe humoral deficiencies and notes uncertain vaccine effectiveness and interference from IVIG. [223]
| Field | Finding |
|---|---|
| Human | Homo sapiens, NCBI Taxonomy 9606; established natural disease |
| Mouse ortholog | Ung, NCBI Gene 22256; experimentally induced knockout models |
| Natural disease in companion/livestock species | No convincing naturally occurring UNG-HIGM5 counterpart identified in OMIA or the veterinary literature searched |
| Breed association | None established; no applicable VBO term |
| Zoonotic potential | None; this is an inherited immunodeficiency |
| Transmission | Mendelian germline transmission, not infectious transmission |
The protein and antibody-diversification mechanism are evolutionarily conserved. Mouse loss of Ung reproduces severe CSR impairment and biased SHM, although residual CSR is greater than in the initial human cases, partly because murine SMUG1 can compensate over time. [298][342]
| Model | Type/resource | Phenotype recapitulated | Principal application and limitation |
|---|---|---|---|
Ung−/− mouse |
Mammalian knockout; MGI/IMSR-searchable | Substantially impaired CSR; G:C mutations shifted to 95% transitions; residual switching remains | Landmark proof of the AID→uracil→UNG model; milder CSR defect than human HIGM5 [299] |
Ung−/−Smug1−/− mouse |
Double knockout | Further loss of residual IgG1 switching and serum IgG3, IgG2b and IgA | Defines SMUG1 compensation; may overstate pathways differently used in humans [298][470] |
Ung−/−Msh2−/− mouse |
Double knockout | Near-complete CSR block and mutation spectrum restricted mainly to transitions at C:G | Separates BER and mismatch-repair contributions |
| CH12F3 mouse B-cell line | In-vitro IgM→IgA-switching model | UNG knockout or inhibition markedly reduces switching | Highly tractable CRISPR system; transformed murine cells do not reproduce whole-patient immunity |
| UNG1/UNG2 isoform-specific CRISPR CH12F3 cells | Functional genomics | Either isoform can support switching in some contexts; dual knockout abolishes switching | Resolves isoform redundancy [314] |
| RPA-binding-helix mutant CH12F3 cells | 2024 CRISPR model | Approximately 80% reduction in IgA-positive cells after stimulation; context-dependent complete failure | Demonstrates RPA-guided recruitment; not yet tied to a human HIGM5 allele [316] |
| Patient EBV-transformed B-cell lines | Human cellular model | Absent UNG activity, excess genomic uracil and failed ssDNA uracil excision | Direct human evidence; EBV transformation may alter expression and metabolism [450] |
| HeLa cells expressing UNG2-F251S | Human in-vitro localization model | Cytoplasmic/mitochondrial mistargeting and poor nuclear accumulation | Explains F251S behavior but is not an activated B cell |
| Human PBMC/BCR repertoire sequencing | Human molecular-profiling model | Reduced G:C transversions and altered A:T mutation pattern | Direct human SHM evidence, but based on one UNG patient [508] |
| DT40 chicken B cells | Avian cellular model | UNG loss/inhibition shifts mutation patterns | Useful for antibody diversification, but species and locus biology differ |
Ung-knockout mice produce only approximately 1–2% IgG1-positive splenic B cells under tested conditions. [16][310]The most defensible interpretation is that HIGM5 is a rare but highly specific failure of specialized DNA-repair machinery co-opted by activated B cells for antibody diversification. The primary clinical problem is antibody failure rather than combined immunodeficiency. Accordingly:
UNG should not be considered diagnostic without biallelic segregation plus functional or compelling phenotype evidence.Overall, the causal gene–disease relationship is strong, but most clinical annotations remain based on fewer than ten well-characterized patients and should be curated with an explicit limited-case-count evidence flag.
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 22 |
| Resolved | 21 |
| Unresolved (possible confabulation) | 1 |
| Unverifiable | 0 |
| References weighed for topical relevance | 21 |
| On topic | 9 |
| Off topic | 1 |
These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:
DOI:10.1371/journal.ppat.1003361&type=printable (1 mention) - Identifier did not resolve to a recordThese identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMC:PMC2952935 (1 mention) - Controlling somatic hypermutation in immunoglobulin variable and switch regions.Weighed against this report's own most characteristic terms: higm5, ung, disease, patient, infection, cell, deficiency, csr, antibody, replacement, uracil, igg, lymphoid, b-cell, immunoglobulin, gene, molecular, recurrent, reduced, iga.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 43 |
| Resolved | 40 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 2 |
| Terms whose name was checked | 20 |
| Terms named correctly | 18 |
| Terms named as a different term | 1 |
| Terms whose name is worth a second look | 1 |
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:
DOID:0060759 (2 mentions) - the report calls it "Disease Ontology"; DOID calls it immunodeficiency with hyper IgM type 5These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0002845 (obsolete Increased proportion of peripheral CD3+ T cells) (1 mention) - replaced by HP:0002851The 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:
GO:0045190 (1 mention) - the report calls it "immunoglobulin class-switch recombination"; GO calls it isotype switching, and lists "class switch recombination" among its other namesTerms 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: ORPHA.