Immunodeficiency 92 (IMD92) is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in REL, which encodes c-Rel, one of the five NF-kB transcription factor subunits. c-Rel binds the promoters of a specific and immunologically coherent set of cytokine genes - IL-2, IFN-gamma, IL-12, IL-21 and IL-23 - so losing it removes transcriptional drive from the IL-12/IFN-gamma axis that controls intracellular-pathogen defence and from the IL-21 signalling that drives B-cell maturation, while leaving the other NF-kB subunits intact. The clinical result matches that transcriptional profile closely. The index patient had susceptibility to Mycobacterium tuberculosis, Salmonella, Cryptosporidium and cytomegalovirus - four intracellular or opportunistic organisms whose control depends on the IL-12/IFN-gamma axis - together with a B-cell arm of reduced IgG, undetectable IgA, a naive-shifted B-cell compartment with almost no switched memory B cells, and non-protective titres to tetanus and diphtheria despite boosters. The second patient adds chronic mucocutaneous candidiasis, chronic CMV viraemia, recurrent HSV-1, shingles, chronic gastrointestinal adenovirus and enterovirus replication, and cholangitis due to Cryptosporidium parvum. The response to BCG vaccination is where the two patients diverge, and it is the most clinically consequential fact in the entry. The index patient received live BCG, poliovirus and measles vaccines without sequelae, and only years later developed femoral M. tuberculosis osteomyelitis. The second patient developed DISSEMINATED BCG disease from the vaccine itself, with bone, lung and lymph node involvement. So the cellular defect is graded rather than absolute - but the grading has observed variance between patients, and live BCG has caused disseminated disease in one of the two vaccinated patients reported. Nothing here supports treating live vaccines as safe in this disease. The disease also has a myeloid arm that the immunodeficiency label does not advertise. Deep immunophenotyping of the second patient showed abolished IL-12 and IL-23 production by conventional type 1 dendritic cells and monocytes but NOT by cDC2s, and loss of CD86 induction on conventional dendritic cells - so c-Rel is required for antigen-presenting function as well as for lymphocyte cytokine output. The cDC1-versus-cDC2 selectivity is the sharpest single result in the disease and is not explained. IMD92 is exceptionally rare. Only three patients have been reported in total, the third in 2026, and the entry is written to keep that visible rather than to read like a characterised syndrome. The evidence is also very unevenly distributed: one patient received an extensive mechanistic workup, while the other two are described clinically. Where a claim rests on a single case, the entry says so in the evidence explanation rather than leaving the reader to infer it from a citation count - and one feature set reported in the third patient (craniosynostosis, language delay, epilepsy) is explicitly novel and unreplicated.
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name: Immunodeficiency 92
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: c-Rel deficiency (immunodeficiency 92)
term:
id: MONDO:0030498
label: immunodeficiency 92
description: >-
Immunodeficiency 92 (IMD92) is an autosomal recessive combined immunodeficiency
caused by biallelic loss-of-function variants in REL, which encodes c-Rel, one of
the five NF-kB transcription factor subunits. c-Rel binds the promoters of a
specific and immunologically coherent set of cytokine genes - IL-2, IFN-gamma,
IL-12, IL-21 and IL-23 - so losing it removes transcriptional drive from the
IL-12/IFN-gamma axis that controls intracellular-pathogen defence and from the
IL-21 signalling that drives B-cell maturation, while leaving the other NF-kB
subunits intact.
The clinical result matches that transcriptional profile closely. The index
patient had susceptibility to Mycobacterium tuberculosis, Salmonella,
Cryptosporidium and cytomegalovirus - four intracellular or opportunistic
organisms whose control depends on the IL-12/IFN-gamma axis - together with a
B-cell arm of reduced IgG, undetectable IgA, a naive-shifted B-cell compartment
with almost no switched memory B cells, and non-protective titres to tetanus and
diphtheria despite boosters. The second patient adds chronic mucocutaneous
candidiasis, chronic CMV viraemia, recurrent HSV-1, shingles, chronic
gastrointestinal adenovirus and enterovirus replication, and cholangitis due to
Cryptosporidium parvum.
The response to BCG vaccination is where the two patients diverge, and it is
the most clinically consequential fact in the entry. The index patient received
live BCG, poliovirus and measles vaccines without sequelae, and only years later
developed femoral M. tuberculosis osteomyelitis. The second patient developed
DISSEMINATED BCG disease from the vaccine itself, with bone, lung and lymph node
involvement. So the cellular defect is graded rather than absolute - but the
grading has observed variance between patients, and live BCG has caused
disseminated disease in one of the two vaccinated patients reported. Nothing
here supports treating live vaccines as safe in this disease.
The disease also has a myeloid arm that the immunodeficiency label does not
advertise. Deep immunophenotyping of the second patient showed abolished IL-12
and IL-23 production by conventional type 1 dendritic cells and monocytes but
NOT by cDC2s, and loss of CD86 induction on conventional dendritic cells - so
c-Rel is required for antigen-presenting function as well as for lymphocyte
cytokine output. The cDC1-versus-cDC2 selectivity is the sharpest single result
in the disease and is not explained.
IMD92 is exceptionally rare. Only three patients have been reported in total, the
third in 2026, and the entry is written to keep that visible rather than to read
like a characterised syndrome. The evidence is also very unevenly distributed:
one patient received an extensive mechanistic workup, while the other two are
described clinically. Where a claim rests on a single case, the entry says so in
the evidence explanation rather than leaving the reader to infer it from a
citation count - and one feature set reported in the third patient
(craniosynostosis, language delay, epilepsy) is explicitly novel and
unreplicated.
parents:
- hereditary disease
- Inborn Error of Immunity
- Combined Immunodeficiency
synonyms:
- IMD92
- c-Rel deficiency
- immunodeficiency due to REL deficiency
- REL deficiency
notes: >-
Evidence base. The entire disease literature is three patients. This has a
practical consequence for reading the entry: `evidence_source: HUMAN_CLINICAL`
here means a single patient, not a cohort - and it means something quite
different again for PMID:34623332, which is a single patient subjected to an
extensive mechanistic workup, and is the strongest evidence in the entry despite
n=1. The schema has no slot that distinguishes any of these, so the distinction
is carried in prose in each `explanation`. See the discussion
`imd92_evidence_base_is_three_cases`.
Scope. The MONDO parent is the broad `immunodeficiency disease`. Once curated,
IMD92 is a candidate member of the existing `kb/groupings/Inborn_Errors_of_Immunity.yaml`
grouping; adding it there is a separate change and is not made in this entry.
Not to be confused with NFKB1 or NFKB2 deficiency, which are commoner NF-kB
pathway inborn errors of immunity presenting as common variable immunodeficiency,
or with the many oncology papers on c-Rel - REL is an established proto-oncogene,
and a literature search on the gene returns mostly cancer biology unrelated to
this disease.
inheritance:
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic REL variants. Both fully described patients were homozygous and born
to consanguineous parents; in the index family the variant was confirmed
heterozygous in both parents and in a healthy brother, which is the segregation
evidence for recessive inheritance.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing confirmed that the mutation is homozygous in the proband and heterozygous in his parents and healthy brother"
explanation: >-
The segregation result establishing recessive inheritance. Note this is a
single family, so it demonstrates recessive segregation in that pedigree
rather than across a series.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Three patients reported in total as of the 2026 report, which described the
third and stated that two had previously been confirmed. No population
prevalence estimate is possible.
evidence:
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Up untill now, only two patients with confirmed pathogenic REL variants have been reported."
explanation: >-
Gives the published case count immediately before this report added the
third. Quoted verbatim including the source's typographical error, as
required for snippet verification.
pathophysiology:
- name: Biallelic Loss-of-Function REL Variants
biological_scale: MOLECULAR
description: >-
The primary lesion is biallelic damage to REL, encoding c-Rel. Three
homozygous alleles are published, all reaching the same endpoint - absent or
severely reduced protein - by different molecular routes, and two of them are
an instructive contrast at the same exon.
The index patient carried a canonical DONOR splice-site variant AFTER exon 5
(c.535+1G>A), which forces use of cryptic donor and acceptor sites and produces
an IN-FRAME transcript lacking 54 nucleotides - 18 residues - within the Rel
homology domain, the DNA-binding and dimerisation module.
The second patient carried the mirror lesion: c.395-1G>A, in the essential
ACCEPTOR splice site of exon 5, common to both known REL isoforms. Skipping
exon 5 there generates a FRAMESHIFT and a premature stop at codon 134. Same
exon, opposite splice boundary, and a different class of consequence.
The third patient carried a homozygous frameshift, c.24del p.(Tyr9Ilefs*2),
introducing a premature stop almost at the start of the coding sequence.
genes:
- preferred_term: REL
term:
id: hgnc:9954
label: REL
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mutant transcript lacks 54 nucleotides encoding 18 residues within the Rel homology domain"
explanation: Characterises the index allele's molecular consequence at transcript level, and locates it in the functionally critical domain.
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "identified a novel homozygous frameshift variant (NM_001291746.4) REL:c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon."
explanation: A further allele class, from the third reported patient, independently confirming that REL loss of function causes the disease.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "located in the essential acceptor splice site of exon 5 common to the 2 known REL isoforms"
explanation: >-
The second patient's allele, c.395-1G>A. It is the mirror of the index
allele - acceptor rather than donor side of the same exon - and it affects
both known REL isoforms.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The skipping of exon 5 is predicted to generate a frameshift and a premature stop codon at position 134 in the mRNA"
explanation: >-
The predicted consequence, and the contrast that matters: the acceptor-side
lesion frameshifts, whereas the index patient's donor-side lesion produced an
in-frame 18-residue deletion.
downstream:
- target: Absent c-Rel Protein
causal_link_type: DIRECT
description: >-
Both alleles abolish or severely reduce c-Rel protein, which is the
functional lesion rather than the transcript change itself.
- name: Absent c-Rel Protein
biological_scale: MOLECULAR
description: >-
Both patients were shown by immunoblot of peripheral blood mononuclear cells to
lack c-Rel protein - absent with no detectable truncation product in the index
patient, severely reduced in the third. The third report adds an important
specificity control: p65 (RelA) levels were preserved, so the lesion is
subunit-selective rather than a general collapse of NF-kB. This is what makes
the disease informative about c-Rel's non-redundant role in humans.
genes:
- preferred_term: REL
term:
id: hgnc:9954
label: REL
biological_processes:
- preferred_term: canonical NF-kappaB signal transduction
modifier: LOSS_OF_FUNCTION
term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
mechanism_confidence: ESTABLISHED
notes: >-
`modifier: LOSS_OF_FUNCTION` rather than `DECREASED` is deliberate here. The
claim is qualitative - one subunit of the canonical NF-kB machinery is missing
while the rest is intact, so the pathway's output is altered in composition,
not merely reduced in amount. The preserved p65 is what licenses that reading.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "immunoblotting using an antibody specific to the protein's N-terminus demonstrated the absence of c-Rel protein in the patient's peripheral blood mononuclear cells (PBMCs) with no detectable truncation products, indicating that the mutation abrogates protein expression"
explanation: Direct protein-level demonstration that the splice allele abolishes c-Rel, closing the gap between genotype and functional deficiency.
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact."
explanation: Independent protein-level confirmation, and the preserved-p65 control establishing that the deficiency is subunit-selective.
downstream:
- target: Failed Transcription of c-Rel-Dependent Cytokine Genes
causal_link_type: DIRECT
description: >-
c-Rel's function is transcriptional, so its absence is read out as failure to
transcribe its promoter targets.
- name: Failed Transcription of c-Rel-Dependent Cytokine Genes
biological_scale: MOLECULAR
description: >-
c-Rel binds the promoters of IL-2, IFN-gamma, IL-12, IL-21 and IL-23. That
target set is not a random collection: IL-12 and IFN-gamma are the axis
controlling macrophage activation against intracellular pathogens, IL-2 drives
T-cell clonal expansion, and IL-21 is the principal T-follicular-helper signal
for B-cell class switching and memory formation. The disease phenotype can be
read almost directly off this promoter list, which is the strongest argument
that the mechanism is correct despite the tiny patient number.
biological_processes:
- preferred_term: positive regulation of transcription by RNA polymerase II
modifier: DECREASED
term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
- preferred_term: interleukin-12 production
modifier: DECREASED
term:
id: GO:0032615
label: interleukin-12 production
mechanism_confidence: ESTABLISHED
notes: >-
This node was drafted as PROVISIONAL on the reasoning that c-Rel's promoter
targets were established from prior immunology but had not been measured in
patient cells. That was wrong: PMID:34623332 measures the output directly in a
c-Rel-deficient patient, and the node is graded ESTABLISHED accordingly. The
measurement is still n=1, but it is a direct measurement rather than an
inference.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "c-Rel binds to the promoters of genes that encode cytokines important for immunity against infectious pathogens, including IL-2, IFN-γ, IL-12, IL-21, and IL-23."
explanation: >-
States the promoter target set this node depends on. This is the report's
background statement of established c-Rel biology rather than a measurement
in the patient; the measurement is the next two items.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s."
explanation: >-
Direct measurement of failed IL-12 and IL-23 output in patient cells - and
the cell-type selectivity, which no promoter-binding argument predicts.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells."
explanation: Direct measurement of the lymphoid cytokine deficit in patient cells, linking reduced IL-2 to the observed proliferation and survival failure.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression."
explanation: >-
Refines the claim rather than simply supporting it - c-Rel is not required
for IL-2 induction as such, only for sustaining it, which is why the T-cell
defect is functional and partial rather than absolute.
downstream:
- target: Myeloid Antigen-Presenting Cell Failure
causal_link_type: DIRECT
description: >-
Loss of IL-12/IL-23 output and of CD86 induction disables the myeloid arm of
the response, independently of anything happening in lymphocytes.
- target: Impaired T Cell Activation and Proliferation
causal_link_type: DIRECT
description: >-
Loss of IL-2 transcription removes the principal autocrine proliferation
signal for activated T cells.
- target: Impaired B Cell Maturation and Class Switching
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Loss of IL-21, a T-cell-derived signal, acts on B cells through the helper
compartment as well as through B-cell-intrinsic c-Rel.
- target: Susceptibility to Intracellular and Opportunistic Pathogens
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Loss of IL-12 and IFN-gamma transcription disables the axis that activates
macrophages against intracellular organisms.
- name: Myeloid Antigen-Presenting Cell Failure
biological_scale: CELLULAR
description: >-
The arm that the phrase "combined immunodeficiency" hides. c-Rel is required in
conventional type 1 dendritic cells and monocytes for IL-12 and IL-23
production, and its loss abolishes that output - while cDC2s are spared. It is
also required for CD86 induction on conventional dendritic cells, so the defect
is not only cytokine secretion but antigen-presenting capacity itself. Since
IL-12 from cDC1s is what licenses Th1 differentiation and IFN-gamma-dependent
macrophage activation, this node explains the mycobacterial and intracellular
susceptibility without needing to invoke a T-cell-intrinsic defect at all -
though the entry models both, because both are measured.
cell_types:
- preferred_term: conventional dendritic cell
term:
id: CL:0000990
label: conventional dendritic cell
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: interleukin-23 production
modifier: ABSENT
term:
id: GO:0032627
label: interleukin-23 production
- preferred_term: antigen processing and presentation
modifier: DECREASED
term:
id: GO:0019882
label: antigen processing and presentation
mechanism_confidence: PROVISIONAL
notes: >-
Graded PROVISIONAL on patient number, not on the quality of the measurement.
The experiments are direct and internally controlled (cDC1 affected, cDC2 not),
but they were performed on one patient's cells.
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s."
explanation: The measurement defining this node, including the cDC1/cDC2 dissociation that makes it a selective rather than global myeloid defect.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs."
explanation: Extends the defect from cytokine output to costimulation and antigen presentation.
downstream:
- target: Susceptibility to Intracellular and Opportunistic Pathogens
causal_link_type: DIRECT
description: >-
Loss of cDC1-derived IL-12 removes the signal that licenses Th1 responses
and IFN-gamma-dependent macrophage activation.
- name: Impaired T Cell Activation and Proliferation
biological_scale: CELLULAR
description: >-
The index patient had numerically increased CD4+ and CD8+ T cells but reduced
memory CD4+CD45RO+ cells and reduced proliferation to phytohaemagglutinin. The
dissociation is informative: T cells are made and survive, but do not respond -
a functional rather than a numerical T-cell defect, which is why the disease
presents as combined immunodeficiency without lymphopenia.
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: T cell proliferation
modifier: DECREASED
term:
id: GO:0042098
label: T cell proliferation
mechanism_confidence: PROVISIONAL
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had increased numbers of CD4+ and CD8+ T cells with decreased memory CD4+CD45RO+ T cells, and reduced proliferation to phytohemagglutinin (PHA)"
explanation: >-
The immunophenotyping and functional proliferation result underlying this
node, from the index patient.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PBMCs from P did not proliferate, or only weakly proliferated, in vitro in response to any of the physiological"
explanation: >-
Independent replication of the proliferation defect in the second patient,
and against PHYSIOLOGICAL antigens rather than a mitogen - the full sentence
lists tuberculin, candidin, tetanus toxoid and CMV antigens, which ties the
T-cell node directly to three of the patient's four infections. The snippet
stops before "stimuli" because the cached text hyphenates that word across a
line break.
- name: Impaired B Cell Maturation and Class Switching
biological_scale: CELLULAR
description: >-
B-cell lymphopenia with impaired proliferation to CD40 ligand plus IL-21,
reduced IgG and undetectable IgA, and non-protective tetanus and diphtheria
titres despite boosters. Immunophenotyping at 9 years showed the compartment
stuck at the naive stage - 85% naive CD19+IgD+CD27- B cells against a normal
range of 47.3-77%, and 0.3% switched memory CD19+CD27+IgD- cells against a
reference range of 10.0-30.4%. The failure of proliferation specifically to
CD40L+IL-21 connects the cellular defect back to the c-Rel-dependent cytokine
IL-21.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: memory B cell
term:
id: CL:0000787
label: memory B cell
biological_processes:
- preferred_term: B cell proliferation
modifier: DECREASED
term:
id: GO:0042100
label: B cell proliferation
mechanism_confidence: PROVISIONAL
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had B cell lymphopenia, impaired B cell proliferation upon stimulation with CD40 ligand + IL-21, reduced IgG and undetectable IgA levels, and non-protective titers to the tetanus and diphtheria vaccines despite booster vaccinations"
explanation: >-
The humoral phenotype, including the IL-21-specific proliferation defect that
links it to the transcriptional node upstream. Single patient.
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "revealed a predominance of naïve CD19+IgD+CD27− B cells (85%; normal 47.3 – 77%) and reduced percentages of switched memory CD19+CD27+IgD− B cells (0.3%; reference range 10.0 – 30.4)"
explanation: Quantifies the maturation block against reference ranges, showing the compartment arrested before class switching.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts."
explanation: >-
Identifies the B-cell-intrinsic transcriptional targets - MYC and BCL2L1 -
whose failed induction blocks plasmablast differentiation, which is a
different and more specific claim than the IL-21 route modelled upstream.
- name: Susceptibility to Intracellular and Opportunistic Pathogens
biological_scale: ORGANISM
description: >-
The clinical endpoint. The index patient's organisms - Mycobacterium
tuberculosis, Salmonella enterica, Cryptosporidium and cytomegalovirus - are
precisely the set controlled by the IL-12/IFN-gamma axis and by cellular
immunity, and the coherence of that list with c-Rel's promoter targets is the
main evidence that the mechanism is right. The second patient's list is broader still - BCG
disease, chronic mucocutaneous candidiasis, cryptosporidiosis, CMV disease and
shingles - and adds a fungal axis that the IL-23/Th17 arm explains.
Chronic cryptosporidiosis led on to cholangitis in BOTH fully described
patients, the classic biliary complication of that organism in
immunodeficiency, which makes it one of the better-replicated features here.
The defect is graded rather than absolute, but the evidence for that is a
DISSOCIATION rather than a uniform observation: the index patient tolerated
live BCG, poliovirus and measles vaccines without sequelae, while the second
patient developed disseminated BCG disease from the vaccine. Both are true, and
the entry does not average them.
mechanism_confidence: ESTABLISHED
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study reports a homozygous mutation in REL abrogating c-Rel protein expression in a patient with combined immunodeficiency characterized by susceptibility to Mycobacterium tuberculosis, Salmonella, Cryptosporidium, and cytomegalovirus."
explanation: The defining infectious susceptibility profile, stated as the report's headline finding.
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He received live vaccinations against poliovirus, measles, and Bacille Calmette-Guerin (BCG) without clinical sequelae."
explanation: >-
One half of the vaccine dissociation: the INDEX patient tolerated live
vaccines, which is not the profile of severe combined immunodeficiency. Read
with the next item, which reports the opposite outcome in the second patient.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "disseminated BCG disease following vaccination (BCG-osis), with bone, lung, and lymph node involvement"
explanation: >-
The other half, and the clinically decisive one: the second patient
developed disseminated disease from the BCG vaccine itself. This is why the
entry does not present live vaccines as tolerated in this disease.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we studied a child with BCG disease, CMC, cryptosporidiosis, CMV disease, and shingles"
explanation: The second patient's infection profile, which is broader than the index patient's and adds the fungal axis.
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections"
explanation: Independent replication of the chronic-diarrhoea-plus-opportunistic-infection presentation in an unrelated patient.
genetic:
- name: REL
gene_term:
preferred_term: REL
term:
id: hgnc:9954
label: REL
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
REL encodes c-Rel, an NF-kB family transcription factor. Inheritance is
autosomal recessive. THREE homozygous alleles are published:
NM_002908.3:c.535+1G>A, a canonical DONOR splice-site variant after exon 5
producing an in-frame 54-nucleotide deletion within the Rel homology domain via
cryptic splice sites; c.395-1G>A, in the essential ACCEPTOR splice site of exon
5 common to both known REL isoforms, where exon-5 skipping frameshifts to a
premature stop at codon 134; and NM_001291746.4:c.24del p.(Tyr9Ilefs*2), a
frameshift creating a very early premature stop. All three patients were from
consanguineous families - Arabic, Moroccan and Moroccan respectively.
The first two are worth reading together: the same exon, opposite splice
boundaries, and different consequence classes (in-frame deletion versus
frameshift), both ending in absent protein.
Functional impact is loss of function for both alleles, demonstrated at protein
level by immunoblot in each case rather than predicted from the variant class.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a homozygous mutation in the canonical donor splice-site after exon 5 of REL (NM_002908.3: c.535+1G>A) was considered the most likely pathogenic variant due to the known contribution of c-Rel in T and B cell activation and cytokine secretion"
explanation: Names the index allele and the reasoning by which it was selected from 80 rare candidate variants.
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This report expands the mutational spectrum of REL and further supports the critical, non-redundant role of c-Rel in human immune homeostasis."
explanation: The second report's own statement of what it adds - an expanded allelic spectrum and support for non-redundancy.
phenotypes:
- category: Immunologic
name: Combined Immunodeficiency
description: >-
Impaired T-cell and B-cell function with preserved or increased T-cell numbers;
a functional combined immunodeficiency rather than a lymphopenic one.
frequency: OBLIGATE
phenotype_term:
preferred_term: Combined immunodeficiency
term:
id: HP:0005387
label: Combined immunodeficiency
evidence:
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene"
explanation: Names the entity and its immunodeficiency character; combined immunodeficiency is the presentation in both fully described patients.
- category: Immunologic
name: Recurrent Mycobacterial Infection
description: >-
Femoral Mycobacterium tuberculosis osteomyelitis at 7 years despite prior BCG
vaccination without sequelae - the signature of an IL-12/IFN-gamma axis defect.
phenotype_term:
preferred_term: Recurrent mycobacterial infections
term:
id: HP:0011274
label: Recurrent mycobacterial infections
notes: >-
Reported in one patient. No frequency is asserted; with three cases in total,
a FrequencyEnum band would be a statistical fiction.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite vaccination with BCG, he developed femoral Mycobacterium tuberculosis osteomyelitis at 7 years of age that was successfully treated with isoniazid, rifampin, pyrazinamide, and ethambutol."
explanation: >-
Documents the mycobacterial disease and its successful treatment. Graded
PARTIAL because a single patient's infection establishes susceptibility as
possible, not as a characteristic disease feature.
- category: Gastrointestinal
name: Chronic Diarrhea
description: >-
Chronic diarrhoea associated with opportunistic enteric infection was the
presenting illness in the index and third patients, in unrelated families.
The second patient's gastrointestinal finding is chronic adenovirus and
enterovirus replication rather than diarrhoea specifically.
phenotype_term:
preferred_term: Chronic diarrhea
term:
id: HP:0002028
label: Chronic diarrhea
temporality: CHRONIC
notes: >-
No frequency band is asserted, for the reason this entry states elsewhere: at
n=3 a FrequencyEnum band is a statistical fiction. Two of three is in any case
FREQUENT, not VERY_FREQUENT, and the description carries the information
honestly without a band.
evidence:
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a third case is described of a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections"
explanation: Chronic diarrhoea as the presenting feature in the third patient, replicating the index presentation.
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 30 months of age, he developed chronic diarrhea associated with multiple infections, including Salmonella enteritica, cytomegalovirus (CMV), and Cryptosporidium."
explanation: The index patient's presenting chronic diarrhoea and its causative organisms.
- category: Hepatobiliary
name: Sclerosing Cholangitis
description: >-
Sclerosing cholangitis with hepatomegaly, developing in the setting of chronic
cryptosporidiosis - a complication of the infection rather than a primary
consequence of c-Rel loss.
phenotype_term:
preferred_term: Sclerosing cholangitis
term:
id: HP:0030991
label: Sclerosing cholangitis
notes: >-
Replicated across both fully described patients, in unrelated families, with
the same aetiology - cryptosporidial biliary infection. That makes it one of
the better-supported features in the entry, despite being secondary to a
treatable infection rather than intrinsic to the mechanism.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the setting of chronic cryptosporidiosis, he developed hepatomegaly and sclerosing cholangitis."
explanation: >-
The index patient's cholangitis, explicitly attributed to the
cryptosporidial infection rather than to c-Rel deficiency directly.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cholangitis due to C. parvum, esophageal candidiasis"
explanation: >-
Independent replication in the second patient, with the same organism -
which is what upgrades this from a single-patient complication to a
reproducible consequence of the immunodeficiency.
- category: Immunologic
name: Decreased Circulating IgG
description: Reduced IgG with undetectable IgA and failure to mount protective vaccine responses.
phenotype_term:
preferred_term: Decreased circulating IgG concentration
term:
id: HP:0004315
label: Decreased circulating IgG concentration
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "reduced IgG and undetectable IgA levels, and non-protective titers to the tetanus and diphtheria vaccines despite booster vaccinations"
explanation: The humoral deficiency and the functional vaccine-response failure. Single patient.
- category: Immunologic
name: Decreased Circulating IgA
description: Undetectable serum IgA in the index patient.
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "reduced IgG and undetectable IgA levels, and non-protective titers to the tetanus and diphtheria vaccines despite booster vaccinations"
explanation: Records the undetectable IgA. Single patient.
- category: Immunologic
name: Disseminated BCG Disease
description: >-
Disseminated disease following BCG vaccination, with bone, lung and lymph node
involvement, in the second patient. This is the entry's most consequential
single clinical fact: the live attenuated vaccine itself caused disseminated
mycobacterial disease.
phenotype_term:
preferred_term: BCGosis
term:
id: HP:0020087
label: BCGosis
notes: >-
One of two BCG-vaccinated patients. The index patient tolerated BCG without
sequelae. Both outcomes are recorded, and no frequency is asserted - see the
discussion `imd92_bcg_dissociation`.
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "disseminated BCG disease following vaccination (BCG-osis), with bone, lung, and lymph node involvement"
explanation: The disseminated BCG disease and its three sites, attributed to the vaccination.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disseminated BCG-osis with bone and lung lesions, cholangitis due to C. parvum, esophageal candidiasis"
explanation: The imaging/clinical summary of the second patient's three defining complications.
- category: Immunologic
name: Chronic Mucocutaneous Candidiasis
description: >-
Chronic mucocutaneous candidiasis including recurrent oesophagitis, in the
second patient. Mechanistically this is the most informative of the second
patient's infections: CMC is the canonical IL-17-axis phenotype, and c-Rel
loss abolishes IL-23 production by cDC1s and impairs Th17 cytokine output by
memory CD4+ T cells - so the fungal susceptibility follows the same
promoter list as the mycobacterial one, one branch further down.
phenotype_term:
preferred_term: Chronic mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
temporality: CHRONIC
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we studied a child with BCG disease, CMC, cryptosporidiosis, CMV disease, and shingles"
explanation: Records CMC among the second patient's defining infections.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells"
explanation: >-
The measured Th17 deficit that connects the candidiasis to the entry's
transcriptional node - the IL-23/Th17 branch of c-Rel's promoter list.
- category: Immunologic
name: Severe Cytomegalovirus Infection
description: Chronic CMV viraemia with recurrent fever in the second patient; CMV disease in the index patient.
phenotype_term:
preferred_term: Severe cytomegalovirus infection
term:
id: HP:0031692
label: Severe cytomegalovirus infection
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we studied a child with BCG disease, CMC, cryptosporidiosis, CMV disease, and shingles"
explanation: CMV disease in the second patient, replicating the index patient's CMV susceptibility.
- category: Immunologic
name: Recurrent Viral Infections
description: >-
Recurrent oral HSV-1 lesions, an episode of thoracic shingles, and chronic
gastrointestinal adenovirus and enterovirus replication in the second patient.
phenotype_term:
preferred_term: Recurrent viral infections
term:
id: HP:0004429
label: Recurrent viral infections
temporality: RECURRENT
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "P had various infections from early childhood onwards: CMC, including recurrent esophagitis; chronic CMV viremia with recurrent fever; recurrent oral herpes simplex virus 1 (HSV-1) lesions"
explanation: The second patient's viral infection profile, listed with the chronicity and recurrence this phenotype records.
- category: Immunologic
name: Reduced Memory Lymphocyte Subsets
description: >-
Deep immunophenotyping showed low frequencies of NK cells, Temra CD8+ T cells,
memory CD4+ T cells including Th1, regulatory T cells and memory B cells, with
other leukocyte subsets normal in count and proportion. The selectivity matters:
this is a defect of differentiated and memory compartments, not a global
lymphopenia.
phenotype_term:
preferred_term: Decreased proportion of memory B cells
term:
id: HP:0030374
label: Decreased memory B cell proportion
notes: >-
The HPO binding captures only the memory-B-cell component. There is no single
HP term for the pattern actually observed - a coordinated reduction across NK,
Temra CD8, memory CD4/Th1, Treg and memory B compartments with other subsets
normal - so the binding necessarily understates the finding, and the
description carries the rest.
evidence:
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal."
explanation: The immunophenotyping result, including the explicit statement that other subsets were normal, which makes the deficit selective.
- category: Skeletal
name: Craniosynostosis
description: >-
Reported in the third patient only, and explicitly flagged by its authors as a
newly reported feature. Whether it belongs to the disease at all is open.
phenotype_term:
preferred_term: Craniosynostosis
term:
id: HP:0001363
label: Craniosynostosis
notes: >-
A single unreplicated observation in a consanguineous child, where a second
recessive condition is a live alternative explanation. Recorded so it can be
checked against future cases, not asserted as a disease feature. See the
discussion `imd92_novel_features_third_patient`.
evidence:
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "alongside newly reported features including craniosynostosis, language delay, and epilepsy"
explanation: >-
Graded PARTIAL. The authors describe these as newly reported; one patient in
a consanguineous family is not sufficient to attribute a non-immunological
feature to REL.
- category: Neurologic
name: Epilepsy
description: Reported in the third patient only, alongside language delay, and unreplicated.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
notes: >-
As for craniosynostosis - single unreplicated report in a consanguineous
child.
evidence:
- reference: PMID:42117340
reference_title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "alongside newly reported features including craniosynostosis, language delay, and epilepsy"
explanation: Same single-patient limitation as craniosynostosis.
treatments:
- name: Immunoglobulin Replacement
description: >-
The supportive standard for a combined immunodeficiency with humoral failure.
The index patient received intravenous immunoglobulin. This is the management
actually reported; it is not disease-specific and no outcome data exist for it
in IMD92.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: immunoglobulin therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
target_mechanisms:
- target: Impaired B Cell Maturation and Class Switching
description: >-
Replacement immunoglobulin substitutes for the antibody the patient's own
arrested B-cell compartment cannot make.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He is currently treated with intravenous immunoglobulin and prophylactic antibiotics while undergoing evaluation for hematopoietic stem cell transplantation."
explanation: >-
Reports the treatment given. It documents practice in one patient, with no
outcome measure, so it establishes what was done rather than that it works.
- name: Antimicrobial Prophylaxis
description: >-
Prophylactic antibiotics alongside immunoglobulin replacement in the index
patient. Split from the immunoglobulin entry so that the modality and the
mechanism it targets are separately queryable - the two interventions address
different arms of the defect.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
target_mechanisms:
- target: Susceptibility to Intracellular and Opportunistic Pathogens
description: >-
Prophylaxis substitutes for the cellular immunity the patient cannot
mount, rather than correcting it.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He is currently treated with intravenous immunoglobulin and prophylactic antibiotics while undergoing evaluation for hematopoietic stem cell transplantation."
explanation: The same sentence documents both arms of the supportive regimen; it reports practice in one patient with no outcome measure.
- name: Hematopoietic Stem Cell Transplantation
description: >-
The curative option, and it has been done. The second patient was transplanted
in 2017 and her infectious phenotypes were cured. The index patient was under
evaluation for transplantation at the time of his report.
The cure is worth more to this entry than a treatment outcome. Because HSCT
replaces only the haematopoietic compartment, simultaneous correction of the
immunological and the infectious phenotypes is a rescue experiment: it
establishes that the disease is caused by intrinsic defects of leukocytes
rather than by anything c-Rel does elsewhere. That is direct support for the
pathograph modelled above, not just for the treatment.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: hematopoietic cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
target_mechanisms:
- target: Absent c-Rel Protein
description: >-
Replacing the haematopoietic compartment with donor cells restores c-Rel
expression in the lineages where it is required.
evidence:
- reference: PMID:31103457
reference_title: Combined immunodeficiency in a patient with c-Rel deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "while undergoing evaluation for hematopoietic stem cell transplantation"
explanation: >-
Graded PARTIAL - it establishes that transplantation was considered
clinically appropriate for the index patient, but reports an evaluation
rather than an outcome. The next item reports the outcome.
- reference: PMID:34623332
reference_title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The simultaneous correction of the immunological and infectious phenotypes by HSCT confirmed that the patient’s immunodeficiency was caused by severe intrinsic defects of leukocytes."
explanation: >-
The cure, and the inference the authors draw from it. Because HSCT replaces
only haematopoietic cells, correcting both phenotypes at once is rescue
evidence that the disease is leukocyte-intrinsic - which supports the whole
pathograph, not only this treatment.
animal_models:
- name: Rel-knockout mouse
species: Mouse
genotype: c-rel-/- (germline inactivation)
publication: PMID:7649478
description: >-
The germline c-rel knockout mouse, described in 1995 - nearly a quarter of a
century before the first human patient, and the reason c-Rel was an immediate
candidate when that patient was sequenced.
modeled_mechanisms:
- target: Impaired T Cell Activation and Proliferation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Rel-/- mice develop all haemopoietic lineages normally but have impaired
humoral immunity and mature B and T cells unresponsive to most mitogens -
the same functional-rather-than-numerical pattern seen in the human patients.
The model additionally locates the defect: exogenous IL-2 restores T-cell but
not B-cell proliferation, so c-Rel regulates different required genes in the
two lineages.
limitations: >-
A mouse null against human alleles that also abolish protein, so the genotype
match is good - but the mouse phenotype is described as a mitogenic-response
defect rather than as susceptibility to mycobacteria and opportunistic
organisms, and the cDC1-selective IL-12 defect that dominates the human
disease was not part of the original murine characterisation.
readouts:
- name: T cell proliferation after exogenous IL-2
target: Impaired T Cell Activation and Proliferation
direction: RESTORED
interpretation: >-
IL-2 rescues the T-cell but not the B-cell proliferative defect, dissecting
the lineage-specific requirement for c-Rel.
evidence:
- reference: PMID:7649478
reference_title: "Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The ability of exogenous interleukin-2 to restore T Cell, but not B cell, proliferation indicates that Rel regulates the expression of different genes in B and T cells that are crucial for cell division and immune function."
explanation: The rescue result and the lineage dissociation it establishes.
evidence:
- reference: PMID:7649478
reference_title: "Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice with an inactivated c-rel gene, whereas development of cells from all hemopoietic lineages appeared normal, humoral immunity was impaired and mature B and T cells were found to be unresponsive to most mitogenic stimuli."
explanation: >-
Establishes the model's core phenotype and, importantly, that lineage
DEVELOPMENT is normal - the same functional-not-numerical signature as the
human disease.
- target: Failed Transcription of c-Rel-Dependent Cytokine Genes
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Rel-/- T cells show impaired cytokine production with normal surface
activation markers, confirming that the lesion is transcriptional rather than
a failure of activation.
limitations: >-
The murine work also shows c-Rel acting as a REPRESSOR in another cell type -
LPS-stimulated Rel-/- macrophages overproduce GM-CSF - so a purely
loss-of-activation model is too simple, and this entry's transcriptional node
does not attempt to capture the repressor role.
evidence:
- reference: PMID:8622948
reference_title: "Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The expression of cell surface markers including the interleukin 2 receptor alpha (IL-2R alpha) chain (CD25), CD69 and L-selectin (CD62) is normal in mitogen-activated Rel-/- T cells, but cytokine production is impaired."
explanation: Separates the transcriptional defect from a failure of activation, since surface activation markers are induced normally.
- reference: PMID:8622948
reference_title: "Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In contrast to mitogen-activated Rel-/- T cells, lipopolysaccharide-stimulated Rel-/- macrophages produce higher than normal levels of GM-CSF."
explanation: >-
Graded PARTIAL because it complicates rather than supports the node -
c-Rel represses as well as activates depending on cell type, which the
entry's transcriptional node does not model.
discussions:
- discussion_id: imd92_evidence_base_is_three_cases
kind: KNOWLEDGE_GAP
attaches_to:
- disease#Immunodeficiency 92
prompt: >-
How much of this entry would survive a fourth and fifth patient?
rationale: >-
Three patients have been reported in total, and only two in enough detail to
curate. Every phenotype except chronic diarrhoea rests on a single individual.
The mechanism is nonetheless unusually credible for such a small series, for
two reasons beyond coherence with c-Rel's promoter targets. Several features
DO replicate across unrelated families - cryptosporidial cholangitis, the
proliferation defect, CMV susceptibility. And the second patient's cure by
HSCT is a rescue result: correcting both the immunological and the infectious
phenotypes by replacing only the haematopoietic compartment establishes the
disease as leukocyte-intrinsic. Readers should treat the pathophysiology chain
as well-motivated and the phenotype frequencies as essentially unknown. This
gap is attached to the disease as a whole because it conditions every claim in
the entry rather than any one of them.
- discussion_id: imd92_novel_features_third_patient
kind: OPEN_QUESTION
attaches_to:
- phenotypes#Craniosynostosis
- phenotypes#Epilepsy
prompt: >-
Are craniosynostosis, language delay and epilepsy part of IMD92, or
coincidental findings in one consanguineous child?
rationale: >-
The third patient's report describes these as newly reported features. Two
things argue for caution. There is no known role for c-Rel in cranial suture
fusion or in neuronal excitability that would predict them, and the patient is
from a consanguineous family, which is exactly the setting in which a second
unrelated recessive disorder is likeliest. Recording them as PARTIAL evidence
with an explicit note is the honest handling: they should be checked against
the next reported patient rather than either dismissed or absorbed into the
phenotype.
- discussion_id: imd92_cdc1_versus_cdc2_selectivity
kind: OPEN_QUESTION
attaches_to:
- pathophysiology#Myeloid Antigen-Presenting Cell Failure
prompt: >-
Why is IL-12/IL-23 production abolished in cDC1s and monocytes but preserved in
cDC2s?
rationale: >-
This is the sharpest result in the disease and the least explained. Both
dendritic-cell subsets express c-Rel and both make IL-12 family cytokines, so a
simple "c-Rel binds the IL12B promoter" account predicts both should fail.
Candidate explanations - a subset-specific difference in NF-kB subunit
redundancy, differing dependence on c-Rel versus RelA at the same promoters, or
a difference in the upstream signals each subset uses - have not been
distinguished. It matters beyond this disease: cDC1 and cDC2 are being targeted
separately in vaccine and cancer immunotherapy design, and a natural human
knockout that separates them is unusually informative.
- discussion_id: imd92_bcg_dissociation
kind: OPEN_QUESTION
attaches_to:
- pathophysiology#Susceptibility to Intracellular and Opportunistic Pathogens
- phenotypes#Disseminated BCG Disease
prompt: >-
Why did BCG vaccination cause disseminated disease in one c-Rel-deficient
patient and no sequelae in another?
rationale: >-
Both fully described patients were BCG-vaccinated. The index patient had no
clinical sequelae and developed femoral M. tuberculosis osteomyelitis only
years later; the second patient developed disseminated BCG disease from the
vaccine, with bone, lung and lymph node involvement. That dissociation is the
strongest available evidence that the cellular defect is graded rather than
absolute - the grading now has observed variance across patients instead of
being inferred from a single tolerant case.
What explains the variance is unknown. The alleles differ (an in-frame
18-residue deletion versus a frameshift at codon 134), so residual protein
function is one candidate; redundancy among NF-kB subunits differing by
individual, host genetic modifiers, and BCG strain or dose are others. Two
patients cannot separate them.
The practical stake is immediate and this entry does not hedge it: live BCG has
caused disseminated disease in one of the two vaccinated c-Rel-deficient
patients reported, so nothing here supports treating live vaccines as safe in
this disease.
references:
- reference: PMID:31103457
title: Combined immunodeficiency in a patient with c-Rel deficiency.
- reference: PMID:42117340
title: A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency-92 With Profound c-Rel Deficiency.
- reference: PMID:34623332
title: Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.
- reference: PMID:7649478
title: "Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression."
- reference: PMID:8622948
title: "Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor."
Disease: Immunodeficiency 92 (IMD92) Cause: Biallelic loss-of-function variants in REL (c-Rel deficiency) Category: Mendelian, autosomal recessive OMIM: #619652 | MONDO: MONDO:0030498 | Gene: REL (HGNC:9954, NCBI Gene 5966, MIM *164910)
Immunodeficiency 92 (IMD92) is an ultra-rare autosomal recessive combined immunodeficiency (CID) caused by biallelic (homozygous) loss-of-function variants in REL, the gene encoding c-Rel, one of the five members of the NF-κB transcription-factor family and a core subunit of the canonical NF-κB pathway. c-Rel is selectively expressed in lymphoid and myeloid cells, where it controls the transcriptional programs required for effective adaptive and innate immunity. When c-Rel is absent, patients develop early-childhood susceptibility to a broad spectrum of viral, bacterial, fungal, and parasitic pathogens, including intracellular organisms such as Mycobacterium tuberculosis, Salmonella, Cryptosporidium, and cytomegalovirus (CMV), typically accompanied by hypogammaglobulinemia and impaired T- and B-cell function.
As of 2026, IMD92 remains exceedingly rare — only three patients from three consanguineous families have been reported worldwide (Beaussant-Cohen 2019; Lévy 2021; El-Hamri 2026). Each patient carried a distinct homozygous REL null allele: a canonical splice-site variant (c.535+1G>A), an undefined loss-of-function allele, and a frameshift (c.24del, p.Tyr9Ilefs*2), respectively. Functional studies across these patients converge on a unified mechanism: c-Rel loss simultaneously cripples myeloid immunity (abolished IL-12/IL-23 production by conventional type-1 dendritic cells [cDC1s] and monocytes; impaired CD86-dependent antigen presentation) and lymphoid immunity (reduced regulatory T cells [Tregs], memory CD4+/CD8+ T cells, NK cells, and memory B cells; defective naive-T-cell IL-2 production; impaired B-cell proliferation and antibody production).
The human phenotype is faithfully recapitulated by the Rel-knockout mouse, which shows impaired humoral immunity, mitogen-unresponsive B and T lymphocytes, and an IL-2–dependent T-cell proliferation defect — establishing a robust, evolutionarily conserved genotype-phenotype relationship. Management follows general combined-immunodeficiency standards: immunoglobulin replacement, anti-infective prophylaxis, and allogeneic hematopoietic stem cell transplantation (HSCT) as the rational curative approach. This report compiles the available evidence across all 15 requested disease-characteristic domains, explicitly flagging the many areas where data do not yet exist for this newly described, ultra-rare disorder.
IMD92 (OMIM #619652) is defined by biallelic loss-of-function variants in REL (chromosome 2p16.1), which encodes the NF-κB subunit c-Rel. The gene identifiers are HGNC:9954, NCBI Gene 5966, and MIM *164910. The index patient carried a homozygous REL null mutation abrogating c-Rel protein expression (Beaussant-Cohen 2019, PMID: 31103457). The most recently reported patient (2026) carried a homozygous frameshift variant, NM_001291746.4:REL:c.24del, p.(Tyr9Ilefs*2), with Western blotting confirming severe c-Rel reduction while p65/RelA was preserved (El-Hamri 2026, PMID: 42117340). The 2026 report states the disorder is "immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene" and "identified a novel homozygous frameshift variant (NM_001291746.4) REL:c.24del p.(Tyr9Ilefs*2)." Only three patients have been reported worldwide, defining IMD92 as an ultra-rare Mendelian inborn error of immunity.
The index patient presented with a combined immunodeficiency characterized by susceptibility to intracellular and opportunistic pathogens — Mycobacterium tuberculosis, Salmonella, Cryptosporidium, and CMV (Beaussant-Cohen 2019, PMID: 31103457). The third patient — a 5-year-old Moroccan child from a consanguineous family — was described as "a 5-year-old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy" (El-Hamri 2026, PMID: 42117340). Whether the neuro-developmental and craniofacial features are core to IMD92 or incidental (e.g., related to consanguinity or a second variant) remains uncertain given the tiny patient number.
c-Rel is one of five NF-κB family members and, per El-Hamri 2026, "c Rel is a key actor of the NF-κB pathway with major implications in the immune response" (PMID: 42117340; see also PMID: 42261849). NF-κB transcription factors have "essential functions... in modulating Treg development and function, with some of these mechanistic insights confirmed by recent studies analyzing Treg cells from patients harboring point mutations in the genes encoding NF-κB proteins" (PMID: 35672519). Mouse studies show Rel-deficient T cells have "defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor" (PMID: 8622948), and c-Rel drives IL-2/IFN-γ transcription while promoting FOXP3/Treg programs (PMID: 41410797).
Beaussant-Cohen 2019 (PMID: 31103457; PMC6688935) described a male proband homozygous for a canonical donor splice-site variant REL NM_002908.3:c.535+1G>A (chr2:61144153 G/A, GRCh37), absent from gnomAD and 1000 Genomes, and heterozygous in unaffected parents and a healthy brother (consistent with autosomal recessive segregation). The mutant transcript uses cryptic splice sites and lacks 54 nucleotides encoding 18 residues within the Rel homology domain, abrogating c-Rel protein. The immunophenotype (age 6) is summarized in the table below.
| Parameter | Finding | Reference range |
|---|---|---|
| WBC | Leukocytosis / lymphocytosis / thrombocytosis | — |
| CD4+ / CD8+ T cells | Increased | — |
| Memory CD4+CD45RO+ T cells | Decreased | — |
| PHA proliferation | 47.3% (reduced) | — |
| B cells | B-cell lymphopenia | — |
| B-cell proliferation (CD40L+IL-21) | 6.4% (impaired) | — |
| IgG | 150 mg/dL | 650–1150 |
| IgM | 150 mg/dL | — |
| IgA | Undetectable | — |
| Anti-diphtheria titer | 0.015 IU/mL (non-protective, despite boosters) | — |
| Switched memory B cells | 0.3% | 10.0–30.4% |
The patient was treated with IVIG plus antibiotic prophylaxis and evaluated for HSCT. The dual role of c-Rel in the immune response underlies this combined immunophenotype ("c Rel is a key actor of the NF-κB pathway with major implications in the immune response", PMID: 42117340).
Lévy et al. 2021 (J Clin Invest 131(17):e150143; PMID: 34623332; Casanova/Puel laboratory) "studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells." This study delineated the dual mechanism:
The patient was from Casablanca, Morocco.
Rel-null mice show normal development of all hematopoietic lineages but "humoral immunity was impaired and mature B and T cells were found to be unresponsive to most mitogenic stimuli" (Köntgen et al. 1995, Genes Dev, PMID: 7649478). Critically, "the ability of exogenous interleukin-2 to restore T cell, but not B cell, proliferation indicates that Rel regulates the expression of different genes in B and T cells." Gerondakis et al. 1996 independently confirmed that "mice lacking Rel are defective in mitogenic activation of B and T lymphocytes and display impaired humoral immunity" (PMID: 8622948). These murine phenotypes match the human patients' impaired PHA/T-cell proliferation, hypogammaglobulinemia, and IL-2 deficit, establishing a conserved genotype–phenotype mechanism.
The pathophysiology of IMD92 flows directly from loss of the c-Rel transcription factor in immune cells:
Biallelic REL LOF (c.535+1G>A / c.24del / other null)
│
▼
Absent / severely reduced c-Rel protein
(Rel homology domain disrupted; p65/RelA preserved)
│
┌───────────────┴────────────────┐
▼ ▼
MYELOID ARM LYMPHOID ARM
• cDC1 + monocyte • ↓ naive-T IL-2 → poor
IL-12/IL-23 abolished proliferation/survival
• ↓ CD86 induction → • ↓ Tregs (FOXP3 program)
impaired antigen • ↓ memory CD4+ (Th1/Th1*),
presentation CD8+ Temra, NK cells
│ • ↓ memory/switched B cells,
│ impaired antibody production
└───────────────┬────────────────┘
▼
Defective Th1 / intracellular-pathogen immunity
+ hypogammaglobulinemia + poor vaccine responses
│
▼
Combined immunodeficiency: susceptibility to viral, bacterial,
fungal, parasitic (M. tuberculosis, Salmonella, Cryptosporidium,
CMV) infections; chronic diarrhea; early childhood onset
Upstream vs downstream: The upstream lesion is transcriptional — loss of c-Rel–dependent gene programs. Downstream consequences are the failure of key cytokine axes, most importantly the IL-12/IL-23 → Th1/IFN-γ axis (explaining mycobacterial and intracellular-pathogen susceptibility) and the IL-2 → T-cell expansion axis — plus impaired humoral immunity. The myeloid defect (antigen-presenting-cell cytokine failure) and the lymphoid defect (intrinsic T/B-cell dysfunction) are additive, producing a broader infection spectrum than a purely lymphoid CID.
Ontology term suggestions: - Gene/Protein: REL / c-Rel (HGNC:9954, UniProt Q04864) - GO biological process: GO:0038061 (canonical NF-κB signal transduction), GO:0042110 (T cell activation), GO:0050852 (T cell receptor signaling pathway), GO:0045066 (regulatory T cell differentiation), GO:0032609 (IFN-γ production), GO:0032735 (positive regulation of IL-12 production), GO:0032747 (positive regulation of IL-23 production) - GO cellular component: GO:0005634 (nucleus), transcription regulator complex - CL cell types: CL:0000451 (dendritic cell), CL:0002399 (CD141-positive/cDC1), CL:0000576 (monocyte), CL:0000815 (regulatory T cell), CL:0000623 (natural killer cell), CL:0000787 (memory B cell), CL:0000897 (memory CD4+ T cell) - UBERON: UBERON:0002371 (bone marrow), UBERON:0002106 (spleen), UBERON:0002509 (mesenteric lymph node), UBERON:0002405 (immune system), UBERON:0000059 (large intestine — chronic diarrhea) - CHEBI (mediators/therapeutics): interleukin-2, interleukin-12, interleukin-23, interferon-gamma, immunoglobulin G - MONDO: MONDO:0030498
IMD92 is an autosomal recessive combined immunodeficiency due to c-Rel deficiency. Key identifiers: OMIM #619652; MONDO:0030498; gene REL (MIM *164910). Orphanet, ICD-10/ICD-11, and MeSH do not yet carry a dedicated code for this ultra-rare entity; it falls under the broad category of combined immunodeficiencies (ICD-10 D81; ICD-11 4A01). Synonyms: c-Rel deficiency; immunodeficiency due to c-Rel deficiency; REL-deficiency combined immunodeficiency. Information is derived from individual patient case reports (three probands) plus aggregated disease-level curation (OMIM) and model-organism data — not from EHR/registry aggregation.
The sole established cause is genetic: biallelic (homozygous) loss-of-function variants in REL. There are no known environmental, infectious, or acquired causes of the underlying deficiency (infections are consequences, not causes). Genetic risk factor: homozygosity for a REL null allele; consanguinity is a major enabling factor — the index (Kuwaiti) and third (Moroccan) families were consanguineous. No susceptibility loci, modifier genes, or protective alleles have been identified (patient numbers too small). No gene–environment interactions have been characterized. Heterozygous carriers appear healthy (parents/siblings were unaffected carriers), consistent with recessive loss-of-function.
| Phenotype | Type | HPO suggestion | Notes / frequency |
|---|---|---|---|
| Recurrent/opportunistic infections | Clinical | HP:0002719 (recurrent infections) | All patients |
| Susceptibility to mycobacteria | Clinical | HP:0032266 (atypical mycobacterial infection) | Index patient |
| CMV / viral disease | Clinical | HP:0011947 | Index + patient 2 |
| Chronic diarrhea | Clinical/GI | HP:0002028 | Patient 3; Cryptosporidium in index |
| Decreased IgG (hypogammaglobulinemia) | Lab | HP:0004315 | IgG 150 mg/dL (index) |
| Decreased IgA | Lab | HP:0002850 | Undetectable (index) |
| Poor specific antibody response | Lab | HP:0005387 | Non-protective diphtheria/tetanus titers |
| Decreased switched memory B cells | Lab | HP:0031381 | 0.3% (ref 10–30%) |
| Reduced T-cell proliferation | Lab | abnormal T-cell proliferation | PHA 47.3% |
| Decreased Tregs / NK / memory T cells | Lab | HP:0410358, HP:0040218 | Patient 2 |
| Craniosynostosis | Physical | HP:0001363 | Patient 3 only (uncertain relatedness) |
| Language delay | Behavioral/neuro | HP:0000750 | Patient 3 only |
| Epilepsy | Clinical/neuro | HP:0001250 | Patient 3 only |
Onset: early childhood (index evaluated at age 6; patient 3 presented at age 5), likely reflecting a congenital immune defect. Severity: severe combined-immunodeficiency phenotype. Progression: chronic/lifelong without curative treatment. Quality of life: substantial impact — recurrent infections, chronic diarrhea, and lifelong immunoglobulin/prophylaxis requirements; formal QoL instruments have not been applied to this ultra-rare cohort.
Causal gene: REL (chr2p16.1; HGNC:9954; NCBI Gene 5966; MIM *164910; UniProt Q04864). Reported pathogenic variants:
| Patient | Variant (nomenclature) | Type | Population frequency | Consequence |
|---|---|---|---|---|
| Index (Beaussant-Cohen 2019) | NM_002908.3:c.535+1G>A | Canonical splice donor | Absent from gnomAD & 1000G | Cryptic splicing; loss of 18 aa in Rel homology domain; no protein |
| Patient 2 (Lévy 2021) | Homozygous REL LOF | Loss-of-function | Rare/absent | Abolished c-Rel; loss of function |
| Patient 3 (El-Hamri 2026) | NM_001291746.4:c.24del, p.(Tyr9Ilefs*2) | Frameshift | Rare/absent | Severe c-Rel reduction; p65/RelA preserved |
All variants are germline, homozygous, loss-of-function (ACMG: pathogenic). No somatic or gain-of-function IMD92 alleles exist. Note the mechanistic contrast: REL 3′-truncations and amplifications are recurrent oncogenic gain-of-function events in lymphoma (PMID: 34695199) — the opposite of the loss-of-function that causes IMD92. No modifier genes, epigenetic drivers, or chromosomal abnormalities have been described for IMD92.
No environmental toxins, radiation, or occupational exposures contribute to disease causation. Infectious agents are downstream consequences, not triggers: Mycobacterium tuberculosis, Salmonella spp., Cryptosporidium spp., cytomegalovirus, and (in patient 2) fungal and parasitic pathogens. Consanguinity (a demographic/social factor) is the principal enabling condition for homozygosity.
Molecular pathway: canonical NF-κB signaling (c-Rel–containing dimers). Cellular processes: T-cell activation/proliferation, Treg differentiation, dendritic-cell/monocyte cytokine production and antigen presentation, B-cell activation and antibody production. Protein dysfunction: loss of function via truncation/splice disruption of the Rel homology domain → absent DNA-binding transcription factor (p65/RelA preserved). Immune involvement: combined (myeloid + lymphoid) immunodeficiency. Key downstream axes: IL-12/IL-23 → Th1/IFN-γ (abolished in cDC1s/monocytes) and IL-2 → T-cell expansion (reduced in naive T cells). Molecular profiling of IMD92 has been limited to targeted immunophenotyping and Western blot; no patient transcriptomic/proteomic/metabolomic datasets are published. See the Mechanistic Model section above for the full causal chain and ontology terms.
Primary system: the immune/hematolymphoid system (UBERON:0002405). Organs/tissues: bone marrow (UBERON:0002371), spleen, lymph nodes, and the thymus-derived T-cell compartment; the gastrointestinal tract (UBERON:0000059, large intestine) via chronic diarrhea/Cryptosporidium. Cell populations: cDC1 (CL:0002399), monocytes (CL:0000576), regulatory T cells (CL:0000815), memory CD4+/CD8+ T cells, NK cells (CL:0000623), memory/switched B cells (CL:0000787). Subcellular: nucleus (GO:0005634) — the site of c-Rel transcriptional activity. In patient 3, additional structures (cranial sutures — craniosynostosis; CNS — epilepsy/language delay) were reported, though their causal link to REL is unconfirmed. Involvement is systemic/bilateral.
Onset: pediatric/early childhood (ages 5–6 at presentation), likely a congenital immune defect manifesting with first infections. Onset pattern: chronic/insidious with recurrent acute infectious episodes. Progression: chronic and lifelong without curative HSCT; progressive infectious morbidity. Critical period: early diagnosis and definitive treatment (HSCT) before accumulation of infection-related organ damage is the key therapeutic window. No spontaneous remission occurs.
Inheritance: autosomal recessive. Penetrance: appears complete in biallelic individuals; carriers unaffected. Expressivity: variable — patient 3 exhibited extra neuro-developmental features. Epidemiology: ultra-rare — only 3 reported patients worldwide (as of 2026); prevalence/incidence not calculable. Founder effects / carrier frequency: unknown; REL LOF alleles are individually private and absent/rare in gnomAD. Consanguinity is central (Kuwaiti and Moroccan consanguineous families). Demographics: reported patients of Middle Eastern (Kuwaiti) and North African (Moroccan) origin; no established sex bias (numbers too small). Genetic anticipation and mosaicism: not applicable/not reported.
Laboratory: immunoglobulin panel (hypogammaglobulinemia — low IgG/IgM, absent IgA); lymphocyte subset flow cytometry (memory B/T, Treg, NK enumeration); specific antibody titers (post-vaccination diphtheria/tetanus — non-protective); lymphocyte proliferation assays (PHA/mitogen, anti-CD3/CD28, CD40L+IL-21). Functional immunology: IL-12/IL-23 production by monocyte-derived/conventional DCs; IL-2 production by naive T cells; c-Rel Western blot (absent protein with preserved p65/RelA is characteristic). Genetic testing (definitive): whole-exome or whole-genome sequencing identifying biallelic REL LOF, confirmed by Sanger sequencing and family segregation. Inborn-errors-of-immunity/CID gene panels that include REL are appropriate. Differential diagnosis: other CIDs and NF-κB-pathway inborn errors of immunity — NFKB1 haploinsufficiency/CVID (PMID: 34473196), RELA haploinsufficiency/dominant-negative disease (PMID: 42261849, PMID: 40876844), RelB deficiency (PMID: 42261849), A20/TNFAIP3 haploinsufficiency (PMID: 34808442) — distinguished by inheritance pattern and immunophenotype. Screening: not on newborn screening panels; cascade/carrier testing feasible within affected families once the variant is known.
Formal survival statistics do not exist for this 3-patient cohort. By analogy to other combined immunodeficiencies, untreated IMD92 carries high infection-related morbidity and mortality; with immunoglobulin replacement and anti-infective prophylaxis, acute risk is reduced, and allogeneic HSCT offers potential cure. Complications include recurrent/opportunistic infections, chronic diarrhea with failure to thrive, and (in patient 3) neurological morbidity. Prognostic factors: timeliness of diagnosis and access to HSCT; degree of pre-transplant infectious organ damage. No validated prognostic biomarkers exist beyond the immunophenotype.
Supportive/standard-of-care (from index patient): immunoglobulin (IVIG) replacement plus antibiotic/anti-infective prophylaxis. Curative: allogeneic hematopoietic stem cell transplantation (HSCT) — the rational definitive therapy for a hematopoietic-intrinsic combined immunodeficiency; the index patient was evaluated for HSCT. Directed anti-infective therapy is used for specific pathogens (anti-mycobacterial, antiviral for CMV, etc.). No approved gene therapy, targeted therapy, or IMD92-specific pharmacotherapy exists, and there are no completed clinical trials (given rarity). NCIT term suggestions: immunoglobulin therapy (NCIT:C583), hematopoietic stem cell transplantation (NCIT:C15431), antibiotic prophylaxis. Pharmacogenomics is not applicable.
Primary prevention of the genetic defect is not possible; preconception/prenatal genetic counseling in consanguineous families with a known REL variant, plus carrier/cascade testing and preimplantation or prenatal genetic diagnosis, can prevent recurrence. Secondary/tertiary prevention in affected patients: infection prophylaxis, immunoglobulin replacement, aggressive early treatment of infections, and timely HSCT to prevent cumulative organ damage. Immunization caveat: live vaccines are contraindicated in combined immunodeficiency, and responses to inactivated vaccines are poor (documented non-protective titers). Genetic counseling per NSGC/ACMG principles is central.
Taxonomy / orthologs: REL is conserved across mammals; the mouse ortholog is Rel (NCBI Gene 19696). No naturally occurring IMD92-equivalent disease has been catalogued in companion animals or wildlife (no OMIA entry noted). Comparative biology: the Rel-knockout mouse (below) demonstrates strong evolutionary conservation of c-Rel's role in lymphocyte activation and humoral immunity. No zoonotic dimension.
The principal model is the Rel-knockout mouse (mammalian germline knockout). It faithfully recapitulates the human disease: normal hematopoietic lineage development but impaired humoral immunity and mature B/T cells unresponsive to most mitogens; PMA+ionomycin bypasses the T-cell proliferation block; exogenous IL-2 restores T- but not B-cell proliferation (Köntgen 1995, PMID: 7649478). Rel-/- T cells show normal activation markers (CD25/CD69/CD62L) but impaired cytokine production and fail to proliferate after anti-CD3/anti-CD28, rescued by IL-2 (Gerondakis 1996, PMID: 8622948). Recapitulation: high for the core immune phenotype (B/T proliferation defect, humoral immunodeficiency, IL-2 dependence). Limitations: mouse models do not capture the human-specific infection spectrum, the neuro-developmental features seen in patient 3, or all human myeloid IL-12/IL-23 nuances. Resources: MGI (Rel); a CRISPR knock-in strategy for conditional human c-Rel expression in mouse T cells has been reported but encountered locus-specific silencing (promoter CpG methylation) challenges (PMID: 41410797).
| PMID | Study | Role in this report |
|---|---|---|
| 31103457 | Beaussant-Cohen 2019 — Combined immunodeficiency in a patient with c-Rel deficiency | First patient; defines disease, splice variant c.535+1G>A, detailed immunophenotype, IVIG+prophylaxis, HSCT evaluation |
| 34623332 | Lévy 2021 (JCI) — Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents | Second patient; defines the dual myeloid (IL-12/IL-23, CD86) + lymphoid (Treg, memory T/B, NK, IL-2) mechanism |
| 42117340 | El-Hamri 2026 — A Novel Biallelic REL Frameshift Variant p.(Tyr9Ilefs*2) Causing IMD92 | Third patient; frameshift variant, profound c-Rel deficiency by Western blot, expanded phenotype (craniosynostosis, epilepsy, language delay); confirms AR inheritance and disease name |
| 7649478 | Köntgen 1995 (Genes Dev) — Rel-null mice | Mouse model recapitulates impaired humoral immunity, mitogen unresponsiveness, IL-2-dependent T-cell rescue |
| 8622948 | Gerondakis 1996 (PNAS) — Rel-deficient T cells | Confirms lymphocyte activation/humoral defects; IL-3/GM-CSF and cytokine production deficits |
| 35672519 | Review — NF-κB in control of regulatory T cell development, identity, and function | Supports c-Rel/NF-κB role in Treg biology, linked to human NF-κB-mutation patients |
| 42261849 | Review — Inborn Errors of Immunity in the NF-κB Pathway | Context: c-Rel within canonical NF-κB; differential diagnosis (RELA, RelB) |
| 41410797 | c-Rel conditional knock-in mouse design | c-Rel drives IL-2/IFN-γ, represses FOXP3; model-engineering resource and caveats |
| 34473196 | NFKB1 variants → AD CVID | Differential diagnosis (contrasting NF-κB inborn error, haploinsufficiency) |
| 34695199 | WGS of adult T-cell leukemia/lymphoma | Contrast: REL 3′-truncations are oncogenic gain-of-function (opposite of IMD92 LOF) |
Evidence source types: human clinical (3 case reports), model organism (mouse knockouts), and in vitro functional immunology (patient cell assays). All primary mechanistic and clinical claims are anchored to the citation snippets validated during the investigation.
Report compiled from 6 confirmed findings and 16 reviewed papers across a 5-iteration autonomous investigation. Evidence base: human clinical case reports (n=3), mouse knockout models, and in vitro patient-cell functional studies.
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