Immunodeficiency 64

Mendelian MONDO:0032803 Pathograph 14 Show in embeddings browser Inborn error of immunity Combined immunodeficiency EBV-susceptibility inborn error of immunity

Immunodeficiency 64 (IMD64; OMIM 618534; RASGRP1 deficiency) is an autosomal recessive combined immunodeficiency with immune dysregulation, caused by biallelic loss-of-function variants in RASGRP1. RASGRP1 is the calcium- and diacylglycerol-regulated guanine nucleotide exchange factor that couples the T cell antigen receptor to RAS, so losing it severs TCR signalling from the RAS-MAPK/ERK cascade at its first step. Roughly fifteen patients have been reported. Infection is essentially universal and lymphoproliferation is present in the large majority; the characteristic and most dangerous complication is EBV-driven B cell lymphoproliferation and lymphoma. What makes the entry mechanistically interesting is that RASGRP1 deficiency is not one lesion but two, running in parallel from the same protein. The expected arm is catalytic: reduced RAS-GTP loading, reduced ERK phosphorylation in both T and B cells, and consequently failed antigen-driven expansion - which is precisely why EBV-specific CD8+ T cells cannot be mobilised to clear infected B cells. The second arm is cytoskeletal and RAS-independent: RASGRP1 interacts with the dynein light chain DYNLL1, deficient cells show decreased RhoA activation, and NK cells fail cytotoxic granule convergence and actin accumulation at the synapse. Lenalidomide restores RhoA activity and reverses the migration and activation defects, which is both a mechanistic argument for the second arm's independence and the only mechanism-based therapy so far proposed. Curators should be aware of a naming hazard: common regulatory variants near RASGRP1 are established GWAS susceptibility alleles for several autoimmune diseases. Those are a different genetic claim from the rare biallelic null alleles that cause IMD64, and literature searches on the gene return both.

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1
Inheritance
8
Pathophys.
13
Phenotypes
1
Hypotheses
2
Gaps
14
Pathograph
1
Genes
4
Medical Actions
6
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
combined immunodeficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
The index kindred was consanguineous with a homozygous stop-gain variant segregating perfectly with disease; subsequently reported patients carry homozygous or compound heterozygous loss-of-function alleles, including homozygous splice-donor variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:27776107 SUPPORT Human Clinical
"In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1."
Healthy consanguineous parents with a biallelic variant in the affected child is the classic autosomal recessive configuration.
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Mechanistic Hypotheses

1
RASGRP1 deficiency acts through parallel catalytic (RAS-ERK) and cytoskeletal (DYNLL1-RhoA) arms
rasgrp1_dual_arm EMERGING
The claim is that the NK synapse and lymphocyte motility defects are not downstream of reduced ERK signalling but arise from a separate RASGRP1 function, mediated by DYNLL1 and read out as reduced RhoA activation. The strongest support is pharmacological rather than genetic: lenalidomide raises RhoA activity and reverses the migration and activation defects without addressing the RAS exchange lesion. If the two arms were serial, a RhoA-directed intervention should not rescue anything.
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Discussions and Knowledge Gaps

2
The defining human phenotype of this disease is EBV-driven B-cell lymphoproliferation, and mice are not susceptible to EBV. What can a mouse model establish about the EBV arm, and what can it not?
HUMAN MODEL MISMATCH OPEN rasgrp1_mouse_cannot_model_ebv
Attached to
pathophysiology#Failed Expansion of EBV-Specific CD8-Positive T Cells pathophysiology#EBV-Driven B Cell Lymphoproliferation and Lymphoma
This is a structural mismatch rather than a fidelity shortfall: the limitation is in the host species, not in how the model was built. Murine Rasgrp1 deficiency produces a systemic-lupus-like autoimmune phenotype, which maps usefully onto this entry's autoimmunity arm, and mouse work has characterised the T-cell developmental requirement for Rasgrp1. Neither can speak to EBV control, because Epstein-Barr virus does not infect mice. The consequence for this entry is specific: the causal chain from failed EBV-specific CD8+ T cell expansion to B-cell lymphoproliferation is supported entirely by human observation plus the shared-mechanism argument across MAGT1, ITK, CD27 and CD70, with no animal system able to test it. Humanised-mouse EBV models exist for other EBV-susceptibility IEIs and are the obvious route.
Show evidence (1 reference)
PMID:42253627 SUPPORT Model Organism
"the systemic lupus erythematosus (SLE)‐like condition observed in RASGRP1‐deficient mice"
The mouse phenotype that is available - autoimmunity - which by contrast makes clear which arm of the human disease has no animal counterpart.
Does lenalidomide's reversal of the RhoA, migration and activation defects in RASGRP1-deficient cells translate into clinical benefit in patients?
KNOWLEDGE GAP OPEN rasgrp1_lenalidomide_translational_gap
Attached to
treatments#Lenalidomide pathophysiology#Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
The lenalidomide result is an ex vivo cellular rescue reported in the original description. No trial, cohort, or case series establishing clinical benefit in RASGRP1 deficiency has been reported, and the 2026 systematic review states that transplantation remains the only curative therapy. The gap is worth recording rather than glossing because a mechanism-based rescue in patient cells is exactly the kind of finding that gets cited as if it were a therapy.
Show evidence (2 references)
PMID:27776107 SUPPORT In Vitro
"Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
The cellular result whose clinical translation is unknown.
PMID:42253627 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation remains the only curative therapy, as conservative management carries high mortality."
Establishes that as of the most recent systematic review no pharmacological therapy, lenalidomide included, is curative.
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Pathophysiology

8
Biallelic RASGRP1 Loss-of-Function Variants
Stop-gain, other truncating, and splice-donor alleles, all biallelic. The structural basis for why truncation is catastrophic is known: RASGRP1 is held autoinhibited, with its RAS-binding catalytic site blocked by an interdomain linker and its membrane-interaction surface buried in a dimerization interface stabilised by the C-terminal oligomerization domain. Calcium binding to the EF-hand regulatory module drives the conformational change that releases it. Truncating alleles remove the catalytic or regulatory modules that convert the calcium/DAG signal into RAS-GTP loading, so there is no partial-activity state to fall back on.
RASGRP1 hgnc:9878 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased RASGRP1 (hgnc:9878). hgnc:9878 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic loss-of-function RASGRP1 alleles - homozygous stop-gain in the index kindred, with subsequently reported truncating and splice-donor alleles.
Downstream
Collapse of TCR-to-RAS-ERK Signal Transduction Loss of the exchange factor that loads RAS with GTP downstream of the TCR.
Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling The same protein loss removes a RAS-independent link to cytoskeletal regulation.
Show evidence (3 references)
PMID:27776107 SUPPORT Human Clinical
"This variant segregated perfectly with the disease and has not been reported in genetic databases."
Perfect segregation plus absence from population databases is the human genetic evidence for causality.
PMID:30030704 SUPPORT Human Clinical
"Genetic screening identified two novel loss-of-function mutations in RASGRP1."
Independent replication of loss-of-function RASGRP1 alleles in unrelated patients.
PMID:23908768 SUPPORT INDIRECT In Vitro
"These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals."
Establishes the autoinhibited architecture whose catalytic and regulatory modules truncating alleles remove. Graded INDIRECT because it characterises wild-type protein architecture, not the patient variants.
Collapse of TCR-to-RAS-ERK Signal Transduction
The catalytic arm. RASGRP1 deficiency reduces RAS-GTPase activity and decreases ERK phosphorylation in both T cells and B cells; re-expression of wild-type RASGRP1 restores ERK phosphorylation, which is what makes this a demonstrated causal step rather than a correlation.
ERK1 and ERK2 cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↓ DECREASED T cell receptor signaling pathway GO:0050852 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. ↓ DECREASED
Ras guanyl-nucleotide exchange factor activity GO:0005085 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves Ras guanyl-nucleotide exchange factor activity, annotated with guanyl-nucleotide exchange factor activity (GO:0005085), qualified as loss of function. GO:0005085 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Defective Antigen-Driven Lymphocyte Proliferation and Activation Loss of the principal proliferative signal downstream of the TCR.
Immune Dysregulation with Autoimmunity and Vasculopathy The same signalling loss that impairs T-cell-dependent viral clearance also impairs B-cell tolerance, so autoimmunity is an output of the central lesion rather than a parallel disease process.
Show evidence (2 references)
PMID:27776107 SUPPORT In Vitro
"RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1."
Reduced ERK phosphorylation in both lineages with wild-type rescue - the core causal demonstration for the catalytic arm.
PMID:30030704 SUPPORT In Vitro
"Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity"
Independent biochemical confirmation, measuring RAS-GTP loading directly rather than inferring it from ERK.
Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
The second, RAS-independent arm. Interaction proteomics identified the dynein light chain DYNLL1 as a RASGRP1 interactor, and RASGRP1-deficient cells show decreased activation of the GTPase RhoA. This is the arm that explains the immune-synapse and motility phenotypes, which do not follow from reduced ERK signalling.
Rho protein signal transduction GO:0007266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Rho protein signal transduction (GO:0007266). GO:0007266 is a biological process from the Gene Ontology. ↓ DECREASED actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired NK Cell Cytotoxic Synapse Assembly Reduced RhoA activity impairs granule convergence and actin accumulation.
Show evidence (2 references)
PMID:27776107 SUPPORT In Vitro
"Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics."
Establishes the physical interaction that is the basis for the cytoskeletal arm.
PMID:27776107 SUPPORT In Vitro
"RASGRP1-deficient cells showed decreased activation of the GTPase RhoA."
The measured signalling consequence of losing the cytoskeletal coupling.
Impaired NK Cell Cytotoxic Synapse Assembly
RASGRP1-deficient NK cells are impaired in cytotoxicity with defective granule convergence and actin accumulation - a synapse-assembly failure rather than a cell-number deficit. Reversible in principle: lenalidomide increases RhoA activity and reverses the migration and activation defects of RASGRP1-deficient lymphocytes.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
natural killer cell mediated cytotoxicity GO:0042267 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased natural killer cell mediated cytotoxicity (GO:0042267). GO:0042267 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:27776107 SUPPORT In Vitro
"RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation."
Locates the NK defect at synapse assembly - granule convergence and actin - rather than at NK cell development or number.
Defective Antigen-Driven Lymphocyte Proliferation and Activation
Proliferation, activation and motility are all defective in T and B cells. Motility is the item worth noticing: it is a cytoskeletal readout appearing alongside the proliferative ones, so both upstream arms converge here.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
positive regulation of T cell proliferation GO:0042102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of T cell proliferation (GO:0042102). GO:0042102 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failed Expansion of EBV-Specific CD8-Positive T Cells Antigen-driven expansion is the specific function EBV control depends on.
Show evidence (1 reference)
PMID:27776107 SUPPORT In Vitro
"RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells."
The cellular phenotype shared by both lymphocyte lineages.
Failed Expansion of EBV-Specific CD8-Positive T Cells
The step that makes IMD64 an EBV disease specifically. RASGRP1 is grouped with MAGT1 and ITK as genes whose mutation causes defective expansion of EBV-specific CD8+ T cells, and therefore failure to eliminate proliferating EBV-infected B cells. This is a shared final common path across a family of inborn errors, reached here through a TCR-proximal signalling defect. Two specific downstream steps are named: loss of RASGRP1 prevents upregulation of CTP synthetase 1 and of the CD27-CD70 axis. Both of those are themselves causes of EBV-susceptibility inborn errors in their own right, which is the concrete reason this disease's oncogenic profile resembles the narrow-spectrum EBV IEIs (CD27, CD70, ITK) rather than the broad lymphoproliferation of ALPS.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Downstream
EBV-Driven B Cell Lymphoproliferation and Lymphoma Unchecked proliferation of EBV-infected B cells.
Lymphoproliferation Failure to clear EBV-infected B cells presents clinically as lymphoproliferative disease.
Show evidence (3 references)
PMID:31402499 SUPPORT Other
"the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK)"
Places RASGRP1 explicitly in the group of T-cell-activation genes whose loss prevents EBV-specific CD8+ T cell expansion.
PMID:37898412 SUPPORT Human Clinical
"T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation"
Directly links the patient's T cell activation defect to failure of EBV control.
PMID:42253627 SUPPORT Human Clinical
"Its absence prevents the upregulation of CTP synthetase 1 and the CD27–CD70 axis, incapacitating the host's ability to manage primary EBV infection"
Names the two specific downstream steps - CTP synthetase 1 and the CD27-CD70 axis - through which loss of RASGRP1 defeats EBV control. Both are themselves the causes of other EBV-susceptibility inborn errors, which is why IMD64 sits with the narrow-spectrum EBV IEIs rather than with the broad lymphoproliferative syndromes.
EBV-Driven B Cell Lymphoproliferation and Lymphoma
The characteristic and most dangerous outcome: EBV-associated lymphoproliferative disease with susceptibility to EBV-induced B cell malignancies.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
EBV-Associated Lymphoma Roughly 40% of reported patients develop B-cell lymphoma, chiefly Hodgkin lymphoma and diffuse large B-cell lymphoma.
Show evidence (1 reference)
PMID:30030704 SUPPORT Human Clinical
"RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
Reports the lymphoproliferative and malignant endpoint together with the autoimmune arm.
Immune Dysregulation with Autoimmunity and Vasculopathy
A second clinical arm, and the one whose weight has grown with reporting. Alongside cytopenic autoimmunity, the 2026 systematic review identifies vascular autoimmunity as an emerging life-threatening phenotype: the index case of that report had severe vasculopathy with ischaemic stroke and thrombosis, secondary antiphospholipid syndrome, and fatal refractory autoimmune haemolytic anaemia. This entry records vasculopathy as emerging rather than established, following the source's own framing. The proposed mechanism is a breakdown of tolerance to vascular antigens, which is the same loss of B-cell tolerance that produces the cytopenic autoantibodies - so the vascular and cytopenic arms are one lesion with two targets, not two findings that happen to co-occur.
Downstream
Autoimmune Hemolytic Anemia Refractory cytopenia, the commonest autoimmune manifestation.
Vasculopathy with Ischemic Stroke Tolerance breakdown extending to vascular antigens, with secondary antiphospholipid syndrome.
Show evidence (2 references)
PMID:42253627 SUPPORT Human Clinical
"We report a 5-year-old male with novel homozygous splice-donor mutations in RASGRP1(c.1720+1G>A and c.1720+2T>C) who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia."
The index case establishing the severity of the vascular and cytopenic-autoimmune arm.
PMID:42253627 SUPPORT Human Clinical
"Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
Quantifies the autoimmune arm across the published cohort and names its usual cytopenic manifestations.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 64 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Blood 6
Lymphoproliferation VERY_FREQUENT Lymphoproliferative disorder HP:0005523 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoproliferative disorder (HP:0005523). HP:0005523 is a phenotype from the Human Phenotype Ontology.
Sequelae: EBV-Associated Lymphoma
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"A review of 14 previously reported cases (plus current case) confirms that while infections (100%) and lymphoproliferation (87%) are common, vascular autoimmunity is an emerging life-threatening phenotype."
Quantifies lymphoproliferation frequency across the aggregated cohort.
EBV-Associated Lymphoma FREQUENT HP:0002665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoma (HP:0002665). HP:0002665 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30030704 SUPPORT Human Clinical
"RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
Reports EBV-induced B cell malignancy as a feature of the disease.
PMID:42253627 SUPPORT Human Clinical
"nearly 40% of the reported patients developed B‐cell lymphomas, including Hodgkin lymphoma (HL) and diffuse large B‐cell lymphoma (DLBCL), so underscoring the role of RASGRP1 in controlling EBV‐driven B‐cell transformation"
Quantifies lymphoma frequency and names the two histologies, which is what the FREQUENT band and the description rest on.
Autoimmune Hemolytic Anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia"
Reports the fatal refractory haemolytic anaemia in the index case.
Deep Venous Thrombosis HP:0002625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep venous thrombosis (HP:0002625). HP:0002625 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"the clinical trajectory was further complicated by the development of deep venous thrombosis (DVT) in the left lower limb and an episode of pulmonary hemorrhage, indicating a systemic prothrombotic and inflammatory condition"
Documents the venous thrombotic event and the authors' reading of it as part of a systemic prothrombotic state.
Immune Thrombocytopenic Purpura Autoimmune thrombocytopenia HP:0001973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Immune thrombocytopenic purpura, annotated with Autoimmune thrombocytopenia (HP:0001973). HP:0001973 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
Names ITP as one of the two characteristic refractory cytopenias.
Thrombotic Thrombocytopenic Purpura Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombotic thrombocytopenic purpura, annotated with Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Deaths were primarily ascribed to refractory AIHA, thrombotic thrombocytopenic purpura (TTP), or complications of lymphoma."
Names TTP among the primary causes of death in the published cohort.
Cardiovascular 3
Vasculopathy with Ischemic Stroke HP:0001297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke (HP:0001297). HP:0001297 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42253627 SUPPORT Human Clinical
"who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia"
Documents the ischaemic stroke and thrombosis constituting the vasculopathy.
PMID:42253627 SUPPORT Human Clinical
"vascular autoimmunity is an emerging life-threatening phenotype"
The authors' own characterisation of vascular autoimmunity as emerging and life-threatening, which is why this is not recorded as an established core feature.
Splenomegaly and Lymphadenopathy HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Patients frequently endure splenomegaly and lymphadenopathy, which often advance to high‐grade malignancies."
Reports both organomegaly findings and their progression to malignancy.
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Patients frequently endure splenomegaly and lymphadenopathy, which often advance to high‐grade malignancies."
Reports lymphadenopathy as a frequent finding in the cohort.
Immune 2
Recurrent Infections OBLIGATE HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42253627 SUPPORT Human Clinical
"A review of 14 previously reported cases (plus current case) confirms that while infections (100%) and lymphoproliferation (87%) are common, vascular autoimmunity is an emerging life-threatening phenotype."
Quantifies infection frequency across the aggregated published cohort.
PMID:42253627 SUPPORT Human Clinical
"While bacterial sinopulmonary infections are prevalent, with a notable susceptibility to viral pathogens, particularly EBV in 73% of cases and cytomegalovirus (CMV) in 27%."
Breaks the infection burden down by pathogen class, giving the EBV and CMV shares.
Autoimmunity VERY_FREQUENT HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30030704 SUPPORT Human Clinical
"RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
Reports severe autoimmune manifestations as a feature of the disease.
PMID:42253627 SUPPORT Human Clinical
"Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
Quantifies the autoimmune frequency across the cohort.
Other 2
Pan-T-Cell Lymphopenia Decreased total T cell count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total T cell count (HP:0005403). HP:0005403 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Laboratory investigations indicated severe pan‐T‐cell lymphopenia, evidenced by a CD3+ count of 460 cells/µL and a critically low CD4+ T‐cell count of 118 cells/µL."
Reports the T-cell counts underlying this phenotype.
Hodgkin Lymphoma HP:0012189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hodgkin lymphoma (HP:0012189). HP:0012189 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"nearly 40% of the reported patients developed B‐cell lymphomas, including Hodgkin lymphoma (HL) and diffuse large B‐cell lymphoma (DLBCL), so underscoring the role of RASGRP1 in controlling EBV‐driven B‐cell transformation"
Names Hodgkin lymphoma among the reported histologies.
🧬

Genetic Associations

1
RASGRP1
Gene: RASGRP1 hgnc:9878 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RASGRP1 (hgnc:9878). hgnc:9878 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:27776107 SUPPORT Human Clinical
"RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling."
States the normal molecular function whose loss defines the disease.
PMID:30030704 SUPPORT Human Clinical
"Genetic screening identified two novel loss-of-function mutations in RASGRP1."
Independent replication of the gene-disease relationship in unrelated patients.
💊

Medical Actions

4
Conservative Immunosuppressive Management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus. sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest.
Steroids, rituximab and sirolimus, used to control the autoimmune and lymphoproliferative manifestations. Curated because it is what most reported patients actually received, and because its outcome is the comparator that makes the transplantation argument: roughly 45% mortality, with deaths ascribed to refractory AIHA, TTP, or lymphoma complications. In the index case an aggressive multimodal regimen - high-dose methylprednisolone, IVIG, eculizumab, sirolimus, bortezomib and plasmapheresis - failed to control the haemolysis.
Show evidence (2 references)
PMID:42253627 REFUTE Human Clinical
"individuals managed conservatively with immunosuppressive agents (including steroids, rituximab, and sirolimus) faced a mortality rate of roughly 45%"
Recorded as REFUTE against conservative immunosuppression being adequate definitive management. It does not say the drugs have no effect - the review notes conservative approaches may provide temporary control - but the reported mortality is the evidence against relying on them.
PMID:42253627 SUPPORT Human Clinical
"Despite aggressive multimodal rescue therapy consisting of high‐dose methylprednisolone, intravenous immunoglobulin (IVIG), eculizumab, sirolimus, bortezomib, and plasmapheresis, the patient's condition continued to deteriorate"
Documents the intensity of rescue therapy attempted in the index case and its failure, which is what "refractory" means concretely here.
Antiviral Prophylaxis and EBV Surveillance
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: valganciclovir CHEBI:63635 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valganciclovir (CHEBI:63635). CHEBI:63635 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral valganciclovir with regular EBV monitoring, used in a reported patient specifically to pre-empt EBV-driven B-cell lymphoma. This is the one management step aimed at the disease's characteristic mechanism rather than at its consequences.
Show evidence (1 reference)
PMID:37898412 SUPPORT Human Clinical
"the patient will be maintained on oral valganciclovir and monitored regularly for Epstein-Bar Virus infections to avoid the development of Epstein-Bar Virus- induced B cell lymphoma"
Documents antiviral prophylaxis with EBV surveillance as a management plan, with the stated aim of preventing EBV-driven lymphoma. This is one patient's plan, not an outcome, so no efficacy is claimed.
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
The only curative therapy, and the review argues for it as definitive care rather than salvage. Four of four transplanted patients achieved full remission and are alive; conservative management carried roughly 45% mortality. Those are small numbers from a retrospective aggregation of fifteen cases with obvious selection pressures - the sickest patients are the least likely to reach transplant - so the contrast is a strong signal rather than a controlled comparison.
Show evidence (2 references)
PMID:42253627 SUPPORT Human Clinical
"Hematopoietic stem cell transplantation remains the only curative therapy, as conservative management carries high mortality."
States both the curative status of transplantation and the mortality of the alternative.
PMID:42253627 SUPPORT Human Clinical
"Four patients received hematopoietic stem cell transplantation (HSCT), all of whom achieved full clinical remission and are alive."
The outcome data behind the curative claim: four of four transplanted patients in remission and alive. Small numbers, but they are the whole transplanted cohort rather than a selected subset.
Lenalidomide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lenalidomide CHEBI:63791 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lenalidomide (CHEBI:63791). CHEBI:63791 is a therapeutic agent from Chemical Entities of Biological Interest.
Mechanism-based and, so far, entirely preclinical for this disease. Lenalidomide increases RhoA activity and reverses the migration and activation defects of RASGRP1-deficient lymphocytes ex vivo, targeting the cytoskeletal arm rather than the RAS exchange lesion. No clinical benefit has been reported - see the knowledge gap attached to this treatment. It is curated because the mechanistic rationale is specific and testable, not because it is established care.
Mechanism Target:
Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling — Raises RhoA activity, the signalling output lost when RASGRP1-DYNLL1 coupling is absent.
Show evidence (1 reference)
PMID:27776107 SUPPORT In Vitro
"Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
Shows the drug acting on the specific signalling defect of this node, in patient-derived cells.
Show evidence (1 reference)
PMID:27776107 SUPPORT In Vitro
"Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
The ex vivo cellular rescue that is the entire evidence base for this treatment.
🔬

Biochemical Markers

1
Antiphospholipid Antibody Panel
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"A comprehensive autoimmune panel revealed significantly positive results for lupus anticoagulant and elevated titers of anti‐beta‐2 glycoprotein and anti‐cardiolipin antibodies, supporting a diagnosis of secondary antiphospholipid syndrome (APS)"
Documents the three antiphospholipid markers and the resulting diagnosis.
🔬

Diagnosis

3
Lymphocyte Activation and Proliferation Testing
Functional immunology is what distinguishes this from a numerical immunodeficiency: the informative findings are defective proliferation, activation and motility of T and B cells, with reduced ERK phosphorylation on TCR stimulation.
Show evidence (1 reference)
PMID:27776107 SUPPORT In Vitro
"RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells."
These are the functional abnormalities a diagnostic immunology laboratory would demonstrate.
Coagulation and Antiphospholipid Screening
Suggested by the review on the strength of the index case: unexplained neurological or vascular symptoms in a RASGRP1-deficient patient should prompt coagulation screening. Recorded as a suggestion, which is what the source calls it - one case is not a surveillance guideline.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"Individuals with RASGRP1 deficiency may benefit from regular coagulation screening, especially in the presence of unexplained neurological or vascular symptoms."
The authors' own hedged surveillance suggestion, reproduced with its hedge intact.
Molecular Genetic Testing of RASGRP1
Confirmatory. Splice-donor alleles feature among reported genotypes, so canonical splice-site variants should not be dismissed on the basis of coding-region-only analysis.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"We report a 5-year-old male with novel homozygous splice-donor mutations in RASGRP1(c.1720+1G>A and c.1720+2T>C)"
Documents homozygous splice-donor alleles as a reported disease genotype.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Fifteen patients from thirteen unrelated families, primarily of consanguineous Middle Eastern or North African origin, with a median age of symptom onset of 12 months. No incidence or prevalence estimate exists.
Show evidence (1 reference)
PMID:42253627 SUPPORT Human Clinical
"The cohort consists of 15 patients from 13 unrelated families, primarily of consanguineous Middle Eastern or North African origin, with a median age of symptom onset of 12 months."
Gives the published cohort size, family count, ancestry skew and median onset age.
{ }

Source YAML

click to show 
name: Immunodeficiency 64
creation_date: "2026-08-30T19:20:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 64
  term:
    id: MONDO:0032803
    label: immunodeficiency 64
description: >
  Immunodeficiency 64 (IMD64; OMIM 618534; RASGRP1 deficiency) is an autosomal
  recessive combined immunodeficiency with immune dysregulation, caused by
  biallelic loss-of-function variants in RASGRP1. RASGRP1 is the calcium- and
  diacylglycerol-regulated guanine nucleotide exchange factor that couples the
  T cell antigen receptor to RAS, so losing it severs TCR signalling from the
  RAS-MAPK/ERK cascade at its first step. Roughly fifteen patients have been
  reported. Infection is essentially universal and lymphoproliferation is
  present in the large majority; the characteristic and most dangerous
  complication is EBV-driven B cell lymphoproliferation and lymphoma.

  What makes the entry mechanistically interesting is that RASGRP1 deficiency
  is not one lesion but two, running in parallel from the same protein. The
  expected arm is catalytic: reduced RAS-GTP loading, reduced ERK
  phosphorylation in both T and B cells, and consequently failed antigen-driven
  expansion - which is precisely why EBV-specific CD8+ T cells cannot be
  mobilised to clear infected B cells. The second arm is cytoskeletal and
  RAS-independent: RASGRP1 interacts with the dynein light chain DYNLL1,
  deficient cells show decreased RhoA activation, and NK cells fail cytotoxic
  granule convergence and actin accumulation at the synapse. Lenalidomide
  restores RhoA activity and reverses the migration and activation defects,
  which is both a mechanistic argument for the second arm's independence and
  the only mechanism-based therapy so far proposed.

  Curators should be aware of a naming hazard: common regulatory variants near
  RASGRP1 are established GWAS susceptibility alleles for several autoimmune
  diseases. Those are a different genetic claim from the rare biallelic null
  alleles that cause IMD64, and literature searches on the gene return both.

synonyms:
  - IMD64
  - RASGRP1 deficiency
  - combined immunodeficiency due to RASGRP1 deficiency

parents:
  - Inborn error of immunity
  - Combined immunodeficiency
  - EBV-susceptibility inborn error of immunity

classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:42253627
      reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RASGRP1 deficiency is a rare inborn error of immunity characterized by immunodeficiency, autoimmunity, and lymphoproliferation."
      explanation: >
        An inborn error of immunity with autoimmunity and lymphoproliferation,
        placing it in Harrison's immune/rheumatologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:27776107
      reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1"
      explanation: >
        A biallelic Mendelian disorder identified by homozygosity mapping,
        placing it in Harrison's genetics Part.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      Both cellular and humoral compartments are functionally affected - ERK
      phosphorylation is reduced in T cells and B cells alike, and
      proliferation, activation and motility are defective in both - so the
      combined-immunodeficiency placement reflects measured biology rather
      than the disease name. NK cytotoxicity is also impaired, by a separate
      cytoskeletal mechanism.
    evidence:
    - reference: PMID:27776107
      reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells."
      explanation: >-
        Documents functional impairment of both T and B lymphocytes, the basis
        for classifying this as a combined rather than isolated T cell defect.
        Graded IN_VITRO because the quoted result is from assays on patient
        cells, not a clinical observation.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    The index kindred was consanguineous with a homozygous stop-gain variant
    segregating perfectly with disease; subsequently reported patients carry
    homozygous or compound heterozygous loss-of-function alleles, including
    homozygous splice-donor variants.
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1."
    explanation: >
      Healthy consanguineous parents with a biallelic variant in the affected
      child is the classic autosomal recessive configuration.

notes: >
  Fifteen patients from thirteen unrelated families. Where this entry gives a
  percentage it comes from the 2026 systematic review of 14 previously reported
  cases plus one new patient, and the denominator is that aggregated cohort -
  not a population. Median age of symptom onset is 12 months; onset is recorded
  in `prevalence.notes` rather than as an `onset` descriptor on individual
  phenotypes, because the source reports one median for the disease rather than
  per-feature onsets.

  Named Entity Confusion warning for future curators and for dataset/literature
  searches on this gene: common regulatory variants at the RASGRP1 locus are
  replicated GWAS susceptibility alleles for East Asian SLE, rheumatoid
  arthritis, Hashimoto thyroiditis and IgA nephropathy. Those are
  population-level dosage-modifying alleles and a different claim entirely from
  the rare biallelic null alleles that cause IMD64. This entry curates only the
  monogenic disease; the GWAS literature is deliberately not cited as evidence
  for any node here, because a common-variant association at a locus is not
  evidence about a Mendelian mechanism.

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fifteen patients from thirteen unrelated families, primarily of
    consanguineous Middle Eastern or North African origin, with a median age of
    symptom onset of 12 months. No incidence or prevalence estimate exists.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cohort consists of 15 patients from 13 unrelated families, primarily of consanguineous Middle Eastern or North African origin, with a median age of symptom onset of 12 months."
    explanation: >-
      Gives the published cohort size, family count, ancestry skew and median
      onset age.

pathophysiology:
- name: Biallelic RASGRP1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >
    Stop-gain, other truncating, and splice-donor alleles, all biallelic. The
    structural basis for why truncation is catastrophic is known: RASGRP1 is
    held autoinhibited, with its RAS-binding catalytic site blocked by an
    interdomain linker and its membrane-interaction surface buried in a
    dimerization interface stabilised by the C-terminal oligomerization domain.
    Calcium binding to the EF-hand regulatory module drives the conformational
    change that releases it. Truncating alleles remove the catalytic or
    regulatory modules that convert the calcium/DAG signal into RAS-GTP
    loading, so there is no partial-activity state to fall back on.
  genes:
  - preferred_term: RASGRP1
    term:
      id: hgnc:9878
      label: RASGRP1
    modifier: DECREASED
  genetic_context:
    description: >-
      Biallelic loss-of-function RASGRP1 alleles - homozygous stop-gain in the
      index kindred, with subsequently reported truncating and splice-donor
      alleles.
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This variant segregated perfectly with the disease and has not been reported in genetic databases."
    explanation: >
      Perfect segregation plus absence from population databases is the human
      genetic evidence for causality.
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic screening identified two novel loss-of-function mutations in RASGRP1."
    explanation: >
      Independent replication of loss-of-function RASGRP1 alleles in unrelated
      patients.
  - reference: PMID:23908768
    reference_title: "Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals."
    explanation: >
      Establishes the autoinhibited architecture whose catalytic and
      regulatory modules truncating alleles remove. Graded INDIRECT because it
      characterises wild-type protein architecture, not the patient variants.
    directness: INDIRECT
  downstream:
  - target: Collapse of TCR-to-RAS-ERK Signal Transduction
    description: Loss of the exchange factor that loads RAS with GTP downstream of the TCR.
  - target: Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
    description: >
      The same protein loss removes a RAS-independent link to cytoskeletal
      regulation.

- name: Collapse of TCR-to-RAS-ERK Signal Transduction
  biological_scale: MOLECULAR
  description: >
    The catalytic arm. RASGRP1 deficiency reduces RAS-GTPase activity and
    decreases ERK phosphorylation in both T cells and B cells; re-expression of
    wild-type RASGRP1 restores ERK phosphorylation, which is what makes this a
    demonstrated causal step rather than a correlation.
  molecular_functions:
  - preferred_term: Ras guanyl-nucleotide exchange factor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: DECREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  - preferred_term: T cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1."
    explanation: >
      Reduced ERK phosphorylation in both lineages with wild-type rescue -
      the core causal demonstration for the catalytic arm.
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity"
    explanation: >
      Independent biochemical confirmation, measuring RAS-GTP loading directly
      rather than inferring it from ERK.
  downstream:
  - target: Defective Antigen-Driven Lymphocyte Proliferation and Activation
    description: Loss of the principal proliferative signal downstream of the TCR.
  - target: Immune Dysregulation with Autoimmunity and Vasculopathy
    description: >
      The same signalling loss that impairs T-cell-dependent viral clearance
      also impairs B-cell tolerance, so autoimmunity is an output of the
      central lesion rather than a parallel disease process.
    evidence:
    - reference: PMID:42253627
      reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the loss of RASGRP1\u2010mediated signaling impairs not only T\u2010cell\u2010dependent viral clearance but also B\u2010cell tolerance, leading to the production of diverse autoantibodies"
      explanation: >
        States the mechanistic link from the RASGRP1 signalling lesion to the
        autoimmune arm, which is what makes this an edge rather than a
        coincidence.

- name: Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
  biological_scale: MOLECULAR
  description: >
    The second, RAS-independent arm. Interaction proteomics identified the
    dynein light chain DYNLL1 as a RASGRP1 interactor, and RASGRP1-deficient
    cells show decreased activation of the GTPase RhoA. This is the arm that
    explains the immune-synapse and motility phenotypes, which do not follow
    from reduced ERK signalling.
  biological_processes:
  - preferred_term: Rho protein signal transduction
    modifier: DECREASED
    term:
      id: GO:0007266
      label: Rho protein signal transduction
  - preferred_term: actin cytoskeleton organization
    modifier: DECREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics."
    explanation: >
      Establishes the physical interaction that is the basis for the
      cytoskeletal arm.
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RASGRP1-deficient cells showed decreased activation of the GTPase RhoA."
    explanation: >
      The measured signalling consequence of losing the cytoskeletal coupling.
  downstream:
  - target: Impaired NK Cell Cytotoxic Synapse Assembly
    description: Reduced RhoA activity impairs granule convergence and actin accumulation.

- name: Impaired NK Cell Cytotoxic Synapse Assembly
  biological_scale: CELLULAR
  description: >
    RASGRP1-deficient NK cells are impaired in cytotoxicity with defective
    granule convergence and actin accumulation - a synapse-assembly failure
    rather than a cell-number deficit. Reversible in principle: lenalidomide
    increases RhoA activity and reverses the migration and activation defects
    of RASGRP1-deficient lymphocytes.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell mediated cytotoxicity
    modifier: DECREASED
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation."
    explanation: >
      Locates the NK defect at synapse assembly - granule convergence and
      actin - rather than at NK cell development or number.

- name: Defective Antigen-Driven Lymphocyte Proliferation and Activation
  biological_scale: CELLULAR
  description: >
    Proliferation, activation and motility are all defective in T and B cells.
    Motility is the item worth noticing: it is a cytoskeletal readout appearing
    alongside the proliferative ones, so both upstream arms converge here.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: positive regulation of T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042102
      label: positive regulation of T cell proliferation
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells."
    explanation: >
      The cellular phenotype shared by both lymphocyte lineages.
  downstream:
  - target: Failed Expansion of EBV-Specific CD8-Positive T Cells
    description: >
      Antigen-driven expansion is the specific function EBV control depends
      on.

- name: Failed Expansion of EBV-Specific CD8-Positive T Cells
  biological_scale: CELLULAR
  description: >
    The step that makes IMD64 an EBV disease specifically. RASGRP1 is grouped
    with MAGT1 and ITK as genes whose mutation causes defective expansion of
    EBV-specific CD8+ T cells, and therefore failure to eliminate proliferating
    EBV-infected B cells. This is a shared final common path across a family of
    inborn errors, reached here through a TCR-proximal signalling defect.

    Two specific downstream steps are named: loss of RASGRP1 prevents
    upregulation of CTP synthetase 1 and of the CD27-CD70 axis. Both of those
    are themselves causes of EBV-susceptibility inborn errors in their own
    right, which is the concrete reason this disease's oncogenic profile
    resembles the narrow-spectrum EBV IEIs (CD27, CD70, ITK) rather than the
    broad lymphoproliferation of ALPS.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: "CD8-positive, alpha-beta T cell"
  evidence:
  - reference: PMID:31402499
    reference_title: "Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK)"
    explanation: >
      Places RASGRP1 explicitly in the group of T-cell-activation genes whose
      loss prevents EBV-specific CD8+ T cell expansion.
  - reference: PMID:37898412
    reference_title: "A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation"
    explanation: >
      Directly links the patient's T cell activation defect to failure of EBV
      control.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its absence prevents the upregulation of CTP synthetase 1 and the CD27\u2013CD70 axis, incapacitating the host's ability to manage primary EBV infection"
    explanation: >
      Names the two specific downstream steps - CTP synthetase 1 and the
      CD27-CD70 axis - through which loss of RASGRP1 defeats EBV control.
      Both are themselves the causes of other EBV-susceptibility inborn errors,
      which is why IMD64 sits with the narrow-spectrum EBV IEIs rather than
      with the broad lymphoproliferative syndromes.
  downstream:
  - target: EBV-Driven B Cell Lymphoproliferation and Lymphoma
    description: Unchecked proliferation of EBV-infected B cells.
  - target: Lymphoproliferation
    description: >
      Failure to clear EBV-infected B cells presents clinically as
      lymphoproliferative disease.

- name: EBV-Driven B Cell Lymphoproliferation and Lymphoma
  biological_scale: ORGANISM
  description: >
    The characteristic and most dangerous outcome: EBV-associated
    lymphoproliferative disease with susceptibility to EBV-induced B cell
    malignancies.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
    explanation: >
      Reports the lymphoproliferative and malignant endpoint together with the
      autoimmune arm.
  downstream:
  - target: EBV-Associated Lymphoma
    description: >
      Roughly 40% of reported patients develop B-cell lymphoma, chiefly
      Hodgkin lymphoma and diffuse large B-cell lymphoma.

- name: Immune Dysregulation with Autoimmunity and Vasculopathy
  biological_scale: ORGANISM
  description: >
    A second clinical arm, and the one whose weight has grown with reporting.
    Alongside cytopenic autoimmunity, the 2026 systematic review identifies
    vascular autoimmunity as an emerging life-threatening phenotype: the index
    case of that report had severe vasculopathy with ischaemic stroke and
    thrombosis, secondary antiphospholipid syndrome, and fatal refractory
    autoimmune haemolytic anaemia. This entry records vasculopathy as emerging
    rather than established, following the source's own framing.

    The proposed mechanism is a breakdown of tolerance to vascular antigens,
    which is the same loss of B-cell tolerance that produces the cytopenic
    autoantibodies - so the vascular and cytopenic arms are one lesion with
    two targets, not two findings that happen to co-occur.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 5-year-old male with novel homozygous splice-donor mutations in RASGRP1(c.1720+1G>A and c.1720+2T>C) who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia."
    explanation: >
      The index case establishing the severity of the vascular and
      cytopenic-autoimmune arm.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
    explanation: >
      Quantifies the autoimmune arm across the published cohort and names its
      usual cytopenic manifestations.
  downstream:
  - target: Autoimmune Hemolytic Anemia
    description: Refractory cytopenia, the commonest autoimmune manifestation.
  - target: Vasculopathy with Ischemic Stroke
    description: >
      Tolerance breakdown extending to vascular antigens, with secondary
      antiphospholipid syndrome.

mechanistic_hypotheses:
- hypothesis_group_id: rasgrp1_dual_arm
  hypothesis_label: RASGRP1 deficiency acts through parallel catalytic (RAS-ERK) and cytoskeletal (DYNLL1-RhoA) arms
  status: EMERGING
  description: >
    The claim is that the NK synapse and lymphocyte motility defects are not
    downstream of reduced ERK signalling but arise from a separate RASGRP1
    function, mediated by DYNLL1 and read out as reduced RhoA activation. The
    strongest support is pharmacological rather than genetic: lenalidomide
    raises RhoA activity and reverses the migration and activation defects
    without addressing the RAS exchange lesion. If the two arms were serial,
    a RhoA-directed intervention should not rescue anything.

discussions:
- discussion_id: rasgrp1_mouse_cannot_model_ebv
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failed Expansion of EBV-Specific CD8-Positive T Cells
  - pathophysiology#EBV-Driven B Cell Lymphoproliferation and Lymphoma
  prompt: >-
    The defining human phenotype of this disease is EBV-driven B-cell
    lymphoproliferation, and mice are not susceptible to EBV. What can a mouse
    model establish about the EBV arm, and what can it not?
  rationale: >-
    This is a structural mismatch rather than a fidelity shortfall: the
    limitation is in the host species, not in how the model was built. Murine
    Rasgrp1 deficiency produces a systemic-lupus-like autoimmune phenotype,
    which maps usefully onto this entry's autoimmunity arm, and mouse work has
    characterised the T-cell developmental requirement for Rasgrp1. Neither can
    speak to EBV control, because Epstein-Barr virus does not infect mice. The
    consequence for this entry is specific: the causal chain from failed
    EBV-specific CD8+ T cell expansion to B-cell lymphoproliferation is
    supported entirely by human observation plus the shared-mechanism argument
    across MAGT1, ITK, CD27 and CD70, with no animal system able to test it.
    Humanised-mouse EBV models exist for other EBV-susceptibility IEIs and are
    the obvious route.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the systemic lupus erythematosus (SLE)\u2010like condition observed in RASGRP1\u2010deficient mice"
    explanation: >-
      The mouse phenotype that is available - autoimmunity - which by contrast
      makes clear which arm of the human disease has no animal counterpart.

- discussion_id: rasgrp1_lenalidomide_translational_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Lenalidomide
  - pathophysiology#Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
  prompt: >-
    Does lenalidomide's reversal of the RhoA, migration and activation defects
    in RASGRP1-deficient cells translate into clinical benefit in patients?
  rationale: >-
    The lenalidomide result is an ex vivo cellular rescue reported in the
    original description. No trial, cohort, or case series establishing
    clinical benefit in RASGRP1 deficiency has been reported, and the 2026
    systematic review states that transplantation remains the only curative
    therapy. The gap is worth recording rather than glossing because a
    mechanism-based rescue in patient cells is exactly the kind of finding
    that gets cited as if it were a therapy.
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
    explanation: >-
      The cellular result whose clinical translation is unknown.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation remains the only curative therapy, as conservative management carries high mortality."
    explanation: >-
      Establishes that as of the most recent systematic review no
      pharmacological therapy, lenalidomide included, is curative.

phenotypes:
- category: Infectious
  name: Recurrent Infections
  description: >
    Reported in every patient in the aggregated cohort (100%, 15/15).
    Bacterial sinopulmonary infections are prevalent; the viral burden is
    dominated by EBV (73%) with CMV in 27%.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A review of 14 previously reported cases (plus current case) confirms that while infections (100%) and lymphoproliferation (87%) are common, vascular autoimmunity is an emerging life-threatening phenotype."
    explanation: >
      Quantifies infection frequency across the aggregated published cohort.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While bacterial sinopulmonary infections are prevalent, with a notable susceptibility to viral pathogens, particularly EBV in 73% of cases and cytomegalovirus (CMV) in 27%."
    explanation: >
      Breaks the infection burden down by pathogen class, giving the EBV and
      CMV shares.

- category: Hematologic
  name: Lymphoproliferation
  description: >
    Present in 87% of the aggregated cohort, and typically EBV-associated.
    Splenomegaly and lymphadenopathy are the usual clinical expression, and
    they often advance to high-grade malignancy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A review of 14 previously reported cases (plus current case) confirms that while infections (100%) and lymphoproliferation (87%) are common, vascular autoimmunity is an emerging life-threatening phenotype."
    explanation: >
      Quantifies lymphoproliferation frequency across the aggregated cohort.
  sequelae:
  - target: EBV-Associated Lymphoma
    description: >
      Uncontrolled EBV-driven B cell proliferation carries a risk of frank
      malignancy.

- category: Neoplastic
  name: EBV-Associated Lymphoma
  description: >
    Roughly 40% of reported patients develop B-cell lymphoma, chiefly Hodgkin
    lymphoma and diffuse large B-cell lymphoma. Susceptibility to EBV-induced
    B cell malignancy is a defining risk of the disease and a principal
    indication for transplantation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
    explanation: >
      Reports EBV-induced B cell malignancy as a feature of the disease.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly 40% of the reported patients developed B\u2010cell lymphomas, including Hodgkin lymphoma (HL) and diffuse large B\u2010cell lymphoma (DLBCL), so underscoring the role of RASGRP1 in controlling EBV\u2010driven B\u2010cell transformation"
    explanation: >
      Quantifies lymphoma frequency and names the two histologies, which is
      what the FREQUENT band and the description rest on.

- category: Immunologic
  name: Autoimmunity
  description: >
    Identified in 87% of the aggregated cohort, and part of the core
    description of the disease rather than a late complication. The usual
    expression is refractory cytopenia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies"
    explanation: >
      Reports severe autoimmune manifestations as a feature of the disease.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
    explanation: >
      Quantifies the autoimmune frequency across the cohort.

- category: Hematologic
  name: Autoimmune Hemolytic Anemia
  description: >
    Reported as refractory and fatal in the 2026 index case, in the setting of
    secondary antiphospholipid syndrome. Recorded as a severe single-case
    presentation, not as a cohort frequency.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  severity: SEVERE
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia"
    explanation: >
      Reports the fatal refractory haemolytic anaemia in the index case.

- category: Vascular
  name: Vasculopathy with Ischemic Stroke
  description: >
    Large-vessel disease: the index case had complete occlusion of an M2 branch
    of the left middle cerebral artery with acute infarction. Recorded as
    emerging rather than established - it rests on one case plus the authors'
    assessment of the literature, not on a reported frequency. The venous
    thrombosis in the same patient is curated separately below, because a
    large-vessel arterial occlusion and a limb DVT are different events with
    different implications even when they share a cause.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who presented with severe vasculopathy (ischemic stroke and thrombosis), secondary antiphospholipid syndrome, and fatal refractory autoimmune hemolytic anemia"
    explanation: >
      Documents the ischaemic stroke and thrombosis constituting the
      vasculopathy.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vascular autoimmunity is an emerging life-threatening phenotype"
    explanation: >
      The authors' own characterisation of vascular autoimmunity as emerging
      and life-threatening, which is why this is not recorded as an
      established core feature.

- category: Vascular
  name: Deep Venous Thrombosis
  description: >
    Left lower limb DVT in the index case, occurring during stabilisation after
    the stroke and alongside pulmonary haemorrhage - the combination the
    authors read as a systemic prothrombotic and inflammatory state rather than
    as isolated events.
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical trajectory was further complicated by the development of deep venous thrombosis (DVT) in the left lower limb and an episode of pulmonary hemorrhage, indicating a systemic prothrombotic and inflammatory condition"
    explanation: >
      Documents the venous thrombotic event and the authors' reading of it as
      part of a systemic prothrombotic state.

- category: Hematologic
  name: Splenomegaly and Lymphadenopathy
  description: >
    The usual clinical expression of the lymphoproliferative arm, and the
    substrate from which the high-grade malignancies arise.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients frequently endure splenomegaly and lymphadenopathy, which often advance to high\u2010grade malignancies."
    explanation: >
      Reports both organomegaly findings and their progression to malignancy.

- category: Hematologic
  name: Lymphadenopathy
  description: >
    Curated alongside splenomegaly rather than bundled with it, since the two
    are separately gradeable clinical findings.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients frequently endure splenomegaly and lymphadenopathy, which often advance to high\u2010grade malignancies."
    explanation: >
      Reports lymphadenopathy as a frequent finding in the cohort.

- category: Hematologic
  name: Immune Thrombocytopenic Purpura
  description: >
    One of the two refractory cytopenias named as the usual expression of the
    autoimmune arm, alongside autoimmune haemolytic anaemia.
  phenotype_term:
    preferred_term: Immune thrombocytopenic purpura
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune dysregulation and autoimmunity were identified in 87% of the patients, typically manifesting as refractory cytopenias such as AIHA and immune thrombocytopenic purpura (ITP)."
    explanation: >
      Names ITP as one of the two characteristic refractory cytopenias.

- category: Hematologic
  name: Thrombotic Thrombocytopenic Purpura
  description: >
    Named as one of three primary causes of death in the cohort, with
    refractory AIHA and lymphoma complications. Recorded because a cause of
    death belongs in the entry even though HPO has no thrombotic
    thrombocytopenic purpura term - the binding here is to the closest accurate
    parent, and the specificity is carried in `preferred_term`.
  phenotype_term:
    preferred_term: Thrombotic thrombocytopenic purpura
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deaths were primarily ascribed to refractory AIHA, thrombotic thrombocytopenic purpura (TTP), or complications of lymphoma."
    explanation: >
      Names TTP among the primary causes of death in the published cohort.

- category: Immunologic
  name: Pan-T-Cell Lymphopenia
  description: >
    Severe in the index case: CD3+ 460 cells/uL with a CD4+ count of
    118 cells/uL. This is the numerical counterpart of the functional T-cell
    defect the entry curates upstream - the lesion is not purely functional.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  severity: SEVERE
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations indicated severe pan\u2010T\u2010cell lymphopenia, evidenced by a CD3+ count of 460 cells/\u00b5L and a critically low CD4+ T\u2010cell count of 118 cells/\u00b5L."
    explanation: >
      Reports the T-cell counts underlying this phenotype.

- category: Neoplastic
  name: Hodgkin Lymphoma
  description: >
    One of the two lymphoma histologies reported across the cohort, the other
    being diffuse large B-cell lymphoma. DLBCL has no HPO term, so it is
    recorded in the description of the parent lymphoma phenotype rather than
    given a binding it cannot have.
  phenotype_term:
    preferred_term: Hodgkin lymphoma
    term:
      id: HP:0012189
      label: Hodgkin lymphoma
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly 40% of the reported patients developed B\u2010cell lymphomas, including Hodgkin lymphoma (HL) and diffuse large B\u2010cell lymphoma (DLBCL), so underscoring the role of RASGRP1 in controlling EBV\u2010driven B\u2010cell transformation"
    explanation: >
      Names Hodgkin lymphoma among the reported histologies.

biochemical:
- name: Antiphospholipid Antibody Panel
  notes: >
    Positive lupus anticoagulant with elevated anti-beta-2-glycoprotein and
    anti-cardiolipin titres in the index case, supporting a diagnosis of
    secondary antiphospholipid syndrome. These are the serological markers that
    make the vascular arm an autoimmune process rather than an unexplained
    thrombotic one. Recorded as a single panel rather than three markers
    because the source reports them as one result supporting one diagnosis.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comprehensive autoimmune panel revealed significantly positive results for lupus anticoagulant and elevated titers of anti\u2010beta\u20102 glycoprotein and anti\u2010cardiolipin antibodies, supporting a diagnosis of secondary antiphospholipid syndrome (APS)"
    explanation: >
      Documents the three antiphospholipid markers and the resulting diagnosis.

genetic:
- name: RASGRP1
  gene_term:
    preferred_term: RASGRP1
    term:
      id: hgnc:9878
      label: RASGRP1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    RASGRP1 encodes a calcium- and diacylglycerol-regulated guanine nucleotide
    exchange factor that activates RAS downstream of the T cell antigen
    receptor. The protein is normally autoinhibited, with the RAS-binding site
    blocked by an interdomain linker and the membrane-interaction surface
    buried in a dimerization interface; calcium binding to the EF-hand
    regulatory module releases it. Disease alleles are biallelic and
    loss-of-function - stop-gain, other truncating, and splice-donor.
  review_notes: >-
    Do not conflate with the common regulatory variants at this locus that are
    GWAS susceptibility alleles for SLE, rheumatoid arthritis, Hashimoto
    thyroiditis and IgA nephropathy. Those alter RASGRP1 dosage at population
    level and would be `relationship_type: SUSCEPTIBILITY` against those
    diseases; they are not evidence about IMD64 and are not cited here. No
    ClinGen gene-disease validity assertion for RASGRP1 in IMD64 exists to
    cite, but the human genetics (perfect segregation, absence from
    population databases, independent replication in unrelated kindreds) plus
    wild-type rescue of the ERK defect support CAUSATIVE.
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling."
    explanation: >
      States the normal molecular function whose loss defines the disease.
  - reference: PMID:30030704
    reference_title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic screening identified two novel loss-of-function mutations in RASGRP1."
    explanation: >
      Independent replication of the gene-disease relationship in unrelated
      patients.

diagnosis:
- name: Lymphocyte Activation and Proliferation Testing
  description: >
    Functional immunology is what distinguishes this from a numerical
    immunodeficiency: the informative findings are defective proliferation,
    activation and motility of T and B cells, with reduced ERK phosphorylation
    on TCR stimulation.
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells."
    explanation: >
      These are the functional abnormalities a diagnostic immunology
      laboratory would demonstrate.

- name: Coagulation and Antiphospholipid Screening
  description: >
    Suggested by the review on the strength of the index case: unexplained
    neurological or vascular symptoms in a RASGRP1-deficient patient should
    prompt coagulation screening. Recorded as a suggestion, which is what the
    source calls it - one case is not a surveillance guideline.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with RASGRP1 deficiency may benefit from regular coagulation screening, especially in the presence of unexplained neurological or vascular symptoms."
    explanation: >
      The authors' own hedged surveillance suggestion, reproduced with its
      hedge intact.

- name: Molecular Genetic Testing of RASGRP1
  description: >
    Confirmatory. Splice-donor alleles feature among reported genotypes, so
    canonical splice-site variants should not be dismissed on the basis of
    coding-region-only analysis.
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 5-year-old male with novel homozygous splice-donor mutations in RASGRP1(c.1720+1G>A and c.1720+2T>C)"
    explanation: >
      Documents homozygous splice-donor alleles as a reported disease
      genotype.

treatments:
- name: Conservative Immunosuppressive Management
  description: >
    Steroids, rituximab and sirolimus, used to control the autoimmune and
    lymphoproliferative manifestations. Curated because it is what most
    reported patients actually received, and because its outcome is the
    comparator that makes the transplantation argument: roughly 45% mortality,
    with deaths ascribed to refractory AIHA, TTP, or lymphoma complications.
    In the index case an aggressive multimodal regimen - high-dose
    methylprednisolone, IVIG, eculizumab, sirolimus, bortezomib and
    plasmapheresis - failed to control the haemolysis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals managed conservatively with immunosuppressive agents (including steroids, rituximab, and sirolimus) faced a mortality rate of roughly 45%"
    explanation: >
      Recorded as REFUTE against conservative immunosuppression being adequate
      definitive management. It does not say the drugs have no effect - the
      review notes conservative approaches may provide temporary control - but
      the reported mortality is the evidence against relying on them.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite aggressive multimodal rescue therapy consisting of high\u2010dose methylprednisolone, intravenous immunoglobulin (IVIG), eculizumab, sirolimus, bortezomib, and plasmapheresis, the patient's condition continued to deteriorate"
    explanation: >
      Documents the intensity of rescue therapy attempted in the index case and
      its failure, which is what "refractory" means concretely here.

- name: Antiviral Prophylaxis and EBV Surveillance
  description: >
    Oral valganciclovir with regular EBV monitoring, used in a reported patient
    specifically to pre-empt EBV-driven B-cell lymphoma. This is the one
    management step aimed at the disease's characteristic mechanism rather than
    at its consequences.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valganciclovir
      term:
        id: CHEBI:63635
        label: valganciclovir
  evidence:
  - reference: PMID:37898412
    reference_title: "A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient will be maintained on oral valganciclovir and monitored regularly for Epstein-Bar Virus infections to avoid the development of Epstein-Bar Virus- induced B cell lymphoma"
    explanation: >
      Documents antiviral prophylaxis with EBV surveillance as a management
      plan, with the stated aim of preventing EBV-driven lymphoma. This is one
      patient's plan, not an outcome, so no efficacy is claimed.

- name: Hematopoietic Stem Cell Transplantation
  description: >
    The only curative therapy, and the review argues for it as definitive care
    rather than salvage. Four of four transplanted patients achieved full
    remission and are alive; conservative management carried roughly 45%
    mortality. Those are small numbers from a retrospective aggregation of
    fifteen cases with obvious selection pressures - the sickest patients are
    the least likely to reach transplant - so the contrast is a strong signal
    rather than a controlled comparison.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation remains the only curative therapy, as conservative management carries high mortality."
    explanation: >
      States both the curative status of transplantation and the mortality of
      the alternative.
  - reference: PMID:42253627
    reference_title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients received hematopoietic stem cell transplantation (HSCT), all of whom achieved full clinical remission and are alive."
    explanation: >
      The outcome data behind the curative claim: four of four transplanted
      patients in remission and alive. Small numbers, but they are the whole
      transplanted cohort rather than a selected subset.

- name: Lenalidomide
  description: >
    Mechanism-based and, so far, entirely preclinical for this disease.
    Lenalidomide increases RhoA activity and reverses the migration and
    activation defects of RASGRP1-deficient lymphocytes ex vivo, targeting the
    cytoskeletal arm rather than the RAS exchange lesion. No clinical benefit
    has been reported - see the knowledge gap attached to this treatment. It
    is curated because the mechanistic rationale is specific and testable, not
    because it is established care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lenalidomide
      term:
        id: CHEBI:63791
        label: lenalidomide
  target_mechanisms:
  - target: Loss of RASGRP1-DYNLL1 Cytoskeletal Coupling
    description: >
      Raises RhoA activity, the signalling output lost when RASGRP1-DYNLL1
      coupling is absent.
    evidence:
    - reference: PMID:27776107
      reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
      explanation: >
        Shows the drug acting on the specific signalling defect of this node,
        in patient-derived cells.
  evidence:
  - reference: PMID:27776107
    reference_title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes."
    explanation: >
      The ex vivo cellular rescue that is the entire evidence base for this
      treatment.

references:
- reference: PMID:27776107
  title: "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."
- reference: PMID:30030704
  title: "Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma."
- reference: PMID:31402499
  title: "Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases."
- reference: PMID:37898412
  title: "A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation."
- reference: PMID:42253627
  title: "RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia."
- reference: PMID:23908768
  title: "Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1."
📚

References & Deep Research

References

6
PMID:27776107
RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics.
No top-level findings curated for this source.
PMID:30030704
Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma.
No top-level findings curated for this source.
PMID:31402499
Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases.
No top-level findings curated for this source.
PMID:37898412
A novel homozygous mutation in RASGRP1 that predisposes to immune dysregulation and immunodeficiency associated with uncontrolled Epstein-Barr virus-induced B cell proliferation.
No top-level findings curated for this source.
PMID:42253627
RASGRP1 Deficiency Manifesting as Severe Vasculopathy and Fatal Autoimmune Hemolytic Anemia.
No top-level findings curated for this source.
PMID:23908768
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
Immunodeficiency 64 (IMD64 / RASGRP1 Deficiency): Comprehensive Disease Characteristics Report
openscientist-autonomous 22 citations 2026-08-30T19:01:14.645915

Immunodeficiency 64 (IMD64 / RASGRP1 Deficiency): Comprehensive Disease Characteristics Report

Summary

Immunodeficiency 64 (IMD64; OMIM #618534; MONDO:0030926) is an ultra-rare autosomal-recessive combined immunodeficiency with immune dysregulation caused by biallelic loss-of-function (LOF) mutations in RASGRP1 (RAS guanyl-releasing protein 1; HGNC:9866; gene locus 15q14). RASGRP1 is a calcium- and diacylglycerol (DAG)-regulated RAS guanine-nucleotide exchange factor (RasGEF) that couples the T-cell receptor (TCR) — and other antigen receptors — to the RAS–RAF–MEK–ERK/MAPK signaling cascade. In the resting state the protein is held in an autoinhibited conformation; TCR engagement generates Ca²⁺ and DAG signals that relieve autoinhibition and switch on RAS. When both alleles are non-functional, this switch fails: thymocyte selection, lymphocyte proliferation, activation and motility, and natural-killer (NK)-cell cytotoxicity are all impaired, and — critically — cytotoxic CD8⁺ T cells cannot control Epstein–Barr-virus (EBV)-infected B cells.

Clinically, IMD64 presents in childhood with recurrent/severe infections (reported in 100% of cases), non-malignant lymphoproliferation (~87%), autoimmunity, and a strong predisposition to EBV-driven B-cell lymphoproliferative disease and lymphoma (both Hodgkin and non-Hodgkin). Autoimmune manifestations range from cytopenias (notably autoimmune hemolytic anemia) to an emerging, potentially fatal vasculopathy. The disease is defined at the disease level from aggregated case reports and small cohorts (~15 reported patients worldwide), not from large EHR datasets. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy; conservative management carries high mortality. Mechanism-based experimental options — most notably lenalidomide, which restores RhoA activity and reverses migration/activation defects in patient lymphocytes — have been reported.

This report synthesizes six confirmed findings and 28 reviewed papers into a full disease knowledge-base entry, organized by the 15 requested sections. Where information is unavailable or not applicable for this ultra-rare monogenic disorder (e.g., cancer-style survival curves, veterinary natural disease), this is stated explicitly.

Key Findings

Finding 1 — IMD64 is caused by biallelic loss-of-function RASGRP1 mutations that impair RAS–MAPK/ERK signaling

Homozygosity mapping plus exome sequencing in a consanguineous family identified a biallelic stop-gain variant in RASGRP1 that segregated perfectly with disease. Functionally, RASGRP1 deficiency reduced phosphorylation of ERK in both T and B cells, and this defect was rescued by re-expression of wild-type RASGRP1, establishing causality and the molecular mechanism (Salzer et al., 2016). This was independently confirmed by Somekh et al. (2018), who identified two additional novel LOF mutations and demonstrated, using immunoblotting and active-RAS pull-down assays, perturbed ERK1/2 signaling and reduced RAS-GTPase activity in a Jurkat model.

"we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease" — PMID: 27776107

"RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1" — PMID: 27776107

"Genetic screening identified two novel loss-of-function mutations in RASGRP1. Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity" — PMID: 30030704

Interpretation: The genetic lesion is a bona-fide autosomal-recessive LOF defect, and the downstream consequence — collapse of TCR→RAS→ERK signaling — is the proximate biochemical cause of the immune phenotype.

Finding 2 — RASGRP1 deficiency causes EBV-driven lymphoproliferation and lymphoma via defective cytotoxic T-cell control of infected B cells

Patient T cells show severe activation defects that result in uncontrolled EBV-induced B-cell proliferation (Mansour et al., 2023). Somekh et al. (2018) described patients with immunodeficiency and EBV-associated lymphoproliferative disease and susceptibility to EBV-induced B-cell malignancies. Mechanistically, Latour & Fischer (2019) group RASGRP1 with MAGT1 and ITK as genes whose mutation causes defective expansion of EBV-specific CD8⁺ T cells and impaired elimination of proliferating EBV-infected B cells.

"T cells from the patient showed severe activation defects resulting in uncontrolled Epstein-Bar Virus-induced B cell proliferation" — PMID: 37898412

"the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK)" — PMID: 31402499

"RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies" — PMID: 30030704

Interpretation: EBV susceptibility is not incidental; it is a direct, mechanistically predictable consequence of impaired TCR-driven CD8⁺ effector expansion. This places IMD64 firmly within the family of inborn errors of immunity predisposing to EBV lymphoproliferation (alongside XLP1/SH2D1A, XLP2/XIAP, ITK, MAGT1, CD27, CD70, CTPS1, CORO1A).

Finding 3 — RASGRP1 links TCR signaling to cytoskeletal dynamics via DYNLL1; the NK-cytotoxicity defect is reversible by lenalidomide

Beyond ERK, RASGRP1 deficiency causes defective proliferation, activation and motility of T and B cells, and impaired NK-cell cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as a RASGRP1 interactor, linking RASGRP1 to cytoskeletal dynamics. Deficient cells showed decreased RhoA GTPase activation, and treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects (Salzer et al., 2016).

"RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics" — PMID: 27776107

"Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes" — PMID: 27776107

Interpretation: RASGRP1 has a RAS-ERK–independent, cytoskeletal arm (via DYNLL1/RhoA) that explains the NK immune-synapse and lymphocyte-motility defects. The lenalidomide rescue provides a rational, mechanism-based bridging therapy.

Finding 4 — Across ~15 reported patients, infections (100%) and lymphoproliferation (87%) predominate; vasculopathy is an emerging fatal phenotype and HSCT is the only cure

A 2026 review by Ashari et al. compiled 14 previously reported cases plus one new patient (a 5-year-old male with a novel homozygous splice-donor RASGRP1 mutation). Across this aggregated cohort, infections occurred in 100% and lymphoproliferation in 87% of cases; severe vasculopathy and fatal autoimmune hemolytic anemia are highlighted as emerging life-threatening phenotypes. HSCT remains the only curative therapy.

"A review of 14 previously reported cases (plus current case) confirms that while infections (100%) and lymphoproliferation (87%) are common, vascular autoimmunity is an emerging life-threatening phenotype. Hematopoietic stem cell transplantation remains the only curative therapy, as conservative management carries high mortality." — PMID: 42253627

Interpretation: This provides the best available disease-level quantification of penetrant phenotypes and prognosis, and flags autoimmune vasculopathy as an underrecognized driver of mortality.

Finding 5 — RASGRP1 is a calcium- and DAG-regulated RAS exchange factor held in an autoinhibited state; truncating mutations abolish this catalytic machinery

A crystal structure of a RasGRP1 fragment (Iwig et al., 2013) revealed that the RAS-binding (catalytic REM/CDC25) site is blocked by an interdomain linker and the membrane-interaction surface is hidden within a dimerization interface stabilized by the C-terminal oligomerization domain. NMR showed that Ca²⁺ binding to the EF-hand regulatory module drives conformational changes incompatible with the inactive assembly, so RasGRP1 is maintained inactive but "poised for activation by calcium and membrane-localization signals."

"We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain." — PMID: 23908768

"NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals." — PMID: 23908768

Interpretation: The structure explains why truncating/LOF mutations are catastrophic: they remove the catalytic and/or regulatory modules needed to convert the Ca²⁺/DAG signal into RAS-GTP loading, producing complete loss of exchange activity.

Finding 6 — Common RASGRP1 regulatory variants are autoimmunity susceptibility loci, distinct from the monogenic biallelic-null immunodeficiency

GWAS/immunochip studies associate common RASGRP1 variants with multiple autoimmune diseases: East Asian SLE (Sun et al., 2016), rheumatoid arthritis in Europeans (2016), Hashimoto's thyroiditis / TPOAb (rs7171171 near RASGRP1, OR 1.4), and IgA nephropathy. These are population-level susceptibility alleles that alter RASGRP1 expression/dosage — mechanistically distinct from the rare biallelic LOF alleles that cause IMD64.

"followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6" — PMID: 26808113

"IL6R, BACH2, RASGRP1, TLE3, and IKZF3 are replicated for the first time in an independent European population" — PMID: 26939566

"rs7171171 near RASGRP1 gene (p = 0.0356, OR = 1.4, CI = 1.02-1.92)" — PMID: 27268232

Interpretation: RASGRP1 exhibits an allelic spectrum: partial/dosage perturbation → polygenic autoimmunity; complete biallelic loss → monogenic combined immunodeficiency (IMD64). This dosage sensitivity underscores RASGRP1's central role in immune homeostasis.

Detailed Section-by-Section Report

1. Disease Information

  • Overview: IMD64 is an autosomal-recessive combined immunodeficiency with immune dysregulation, characterized by defective TCR→RAS→ERK signaling, recurrent infections, lymphoproliferation, autoimmunity, and EBV-associated lymphoma.
  • Key identifiers: OMIM #618534 ("Immunodeficiency 64 with lymphoproliferation"); MONDO:0030926; gene RASGRP1 (HGNC:9866; NCBI Gene 10125; OMIM 603962). Orphanet does not have a widely used dedicated ORPHAcode distinct from the RASGRP1-deficiency entry; ICD-11 best maps to 4A00.x* (Primary immunodeficiencies) / immune dysregulation category; MeSH lacks a specific term (falls under "Primary Immunodeficiency Diseases," D000081207; "Lymphoproliferative Disorders," D008232).
  • Synonyms / alternative names: "Immunodeficiency 64 with lymphoproliferation"; "RASGRP1 deficiency"; "RASGRP1-related combined immunodeficiency."
  • Information source: Aggregated disease-level knowledge derived from individual case reports and small case series (~15 patients), not from large-scale EHR/registry data.

2. Etiology

  • Primary cause: Genetic — biallelic loss-of-function mutations in RASGRP1 (Finding 1). No environmental or infectious cause initiates the disease, though EBV acts as a critical downstream trigger of lymphoproliferation/lymphoma in the setting of the genetic defect (Finding 2).
  • Genetic risk factors: The causal variants are private/rare biallelic RASGRP1 LOF alleles (stop-gain, splice-site, frameshift). Consanguinity is a major risk factor, as most reported families are consanguineous with homozygous variants (Findings 1, 4). Common RASGRP1 regulatory variants are not a cause of IMD64 but are independent autoimmunity susceptibility alleles (Finding 6).
  • Environmental risk factors: EBV exposure (near-universal in humans) is the key environmental cofactor converting the immunodeficiency into life-threatening lymphoproliferation.
  • Protective factors: None established genetically. Practically, EBV surveillance and avoidance of unnecessary immunosuppression may reduce complications; no protective alleles are known.
  • Gene–environment interaction: The central GxE interaction is RASGRP1 LOF × EBV infection → uncontrolled B-cell proliferation and lymphoma (Findings 2, 4).

3. Phenotypes

Phenotype Type HPO term (suggested) Frequency Onset / severity
Recurrent/severe infections Clinical / immunologic HP:0002719 (Recurrent infections) 100% Childhood; moderate–severe
Non-malignant lymphoproliferation (lymphadenopathy, splenomegaly) Clinical sign HP:0002733 (Generalized lymphadenopathy); HP:0001744 (Splenomegaly) ~87% Childhood; variable
EBV-driven lymphoproliferative disease / lymphoma (Hodgkin & non-Hodgkin) Neoplasm HP:0002665 (Lymphoma); HP:0005523 (Combined immunodeficiency) High Childhood/adolescence; severe
Autoimmune cytopenias (autoimmune hemolytic anemia) Lab / clinical HP:0001890 (Autoimmune hemolytic anemia) Recurrent Childhood; can be fatal
Vasculopathy / vascular autoimmunity Clinical HP:0002597 (Abnormality of the vasculature) Emerging Severe, potentially fatal
Impaired T/B-cell proliferation & activation; abnormal lymphocyte subsets Lab abnormality HP:0005425 (Abnormal T cell count); HP:0010975 (Abnormal B cell morphology) Common Congenital defect, childhood-detected
Reduced NK cytotoxicity Lab abnormality HP:0012177 (Decreased proportion of NK cells) Common Congenital
Hypogammaglobulinemia / absent B cells (subset) Lab abnormality HP:0004313 (Decreased circulating antibody level) Variable Childhood
  • Progression: Generally progressive/episodic, punctuated by infection and autoimmune flares; lymphoma is a life-threatening event.
  • Quality-of-life impact: Substantial — recurrent hospitalization for infection, immunosuppression, chemotherapy, and transplant; disease-specific QoL instruments (EQ-5D/SF-36) have not been reported for this ultra-rare disorder.

4. Genetic / Molecular Information

  • Causal gene: RASGRP1 (HGNC:9866; NCBI Gene 10125; OMIM *603962; Ensembl ENSG00000172575; 15q14; UniProt O95267).
  • Pathogenic variants: Reported variants are biallelic LOF: stop-gain/nonsense (Salzer 2016), splice-donor (Ashari 2026), frameshift, and other LOF alleles (Somekh 2018). Classification per ACMG/AMP is pathogenic/likely pathogenic for these truncating and splice variants (PVS1-supporting, given LOF is the established disease mechanism).
  • Variant type/class: Nonsense, splice-site, frameshift (loss-of-function); the disease requires homozygous or compound-heterozygous LOF.
  • Allele frequency: Causal alleles are extremely rare/private (absent or ultra-rare in gnomAD), consistent with recessive, often consanguineous inheritance.
  • Somatic vs germline: Germline (constitutional). Secondary lymphomas may acquire somatic changes, but the primary lesion is germline.
  • Functional consequence: Loss of function — abolition of RAS-GEF catalytic activity and Ca²⁺/DAG-regulated activation (Findings 1, 5).
  • Modifier genes: Not formally defined; disease severity may be modulated by EBV status and other immune genes, but no specific modifiers proven.
  • Epigenetic information: RASGRP1 expression is transcriptionally regulated (e.g., Nurr1 binds a RasGRP1 intron; PMID: 32612143), but disease-specific epigenetic changes in IMD64 are not established.
  • Chromosomal abnormalities: None characteristic; IMD64 is a single-gene disorder, not a copy-number/aneuploidy syndrome.

5. Environmental Information

  • Environmental factors: No toxic/occupational/radiation exposures cause IMD64.
  • Lifestyle factors: Not applicable as causal factors.
  • Infectious agents: Epstein–Barr virus (EBV; HHV-4; NCBI Taxon 10376) is the pivotal infectious trigger of lymphoproliferation and lymphoma (Findings 2, 4). Patients are also generally susceptible to recurrent bacterial and other viral infections due to combined immunodeficiency.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Biallelic RASGRP1 LOF mutation
│  (loss of Ca2+/DAG-regulated RasGEF; catalytic/regulatory modules abolished — Iwig 2013)
▼
Failure to load RAS-GTP after TCR/pre-TCR engagement
│
▼
Collapse of RAS → RAF → MEK → ERK1/2 (MAPK) signaling  (Salzer 2016; Somekh 2018)
│                                   │
▼                                   ▼
Impaired thymocyte positive selection    Defective lymphocyte proliferation/activation
(reduced naive T-cell output)                 + RASGRP1–DYNLL1–RhoA cytoskeletal arm
│                                   │        (impaired motility; NK granule
▼                                   ▼         convergence & actin — Salzer 2016)
Reduced/abnormal T-cell repertoire      Defective CD8+ effector expansion & NK cytotoxicity
│                                   │
└───────────────┬───────────────────┘
        ▼
Failure to control EBV-infected B cells
        ▼
   Uncontrolled B-cell proliferation → lymphoproliferative disease → Hodgkin/non-Hodgkin lymphoma
        ▼
   Concurrent loss of tolerance → autoimmunity (AIHA, cytopenias, vasculopathy)
  • Molecular pathways: RAS–MAPK/ERK (KEGG hsa04014; Reactome RAF/MAP kinase cascade R-HSA-5673001); TCR signaling (KEGG hsa04660); DAG/Ca²⁺ second-messenger signaling. RASGRP1 sits upstream, converting DAG/Ca²⁺ to RAS activation; adaptors such as SKAP55 (PMID: 17658605) modulate RASGRP1.
  • Cellular processes (GO suggestions): GO:0007265 (Ras protein signal transduction), GO:0000165 (MAPK cascade), GO:0050852 (T cell receptor signaling pathway), GO:0042110 (T cell activation), GO:0002323 (natural killer cell activation), GO:0030036 (actin cytoskeleton organization), GO:0007204 (positive regulation of cytosolic calcium ion concentration).
  • Protein dysfunction: Loss of RAS-GEF catalytic function; truncating mutations remove REM/CDC25 catalytic and/or EF-hand/C1 regulatory modules, abolishing Ca²⁺/DAG-triggered relief of autoinhibition (Finding 5).
  • Immune-system involvement: Combined immunodeficiency (impaired T, B, NK function) plus immune dysregulation/autoimmunity — a hallmark "PIRD" (primary immune regulatory disorder).
  • Cell types (CL suggestions): CL:0000084 (T cell), CL:0000625 (CD8⁺ T cell), CL:0000624 (CD4⁺ T cell), CL:0000236 (B cell), CL:0000623 (natural killer cell), CL:0000813 (memory T cell).
  • Molecular profiling: Functional immunology (pERK, RAS-GTP pull-down, NK cytotoxicity assays) is the main readout; no large transcriptomic/proteomic/metabolomic disease signatures have been published.

7. Anatomical Structures Affected

  • Organ level: Immune/lymphoid system primarily — thymus (UBERON:0002370; impaired selection), spleen (UBERON:0002106; splenomegaly), lymph nodes (UBERON:0000029; lymphadenopathy), bone marrow (UBERON:0002371). Secondary involvement: blood vessels (UBERON:0001981; vasculopathy), kidney (UBERON:0002113; diffuse mesangial sclerosis/nephrotic syndrome reported — PMID: 39752212), and red-cell compartment (AIHA).
  • Body systems: Immune/hematolymphoid (primary); cardiovascular (vasculopathy); renal (secondary).
  • Tissue/cell level: Hematopoietic/lymphoid tissue; affected populations are T cells, B cells, and NK cells (CL terms above).
  • Subcellular level (GO cellular component): GO:0005886 (plasma membrane; site of RAS activation), GO:0005856 (cytoskeleton; DYNLL1/RhoA arm), GO:0005768 (endosome; RasGRP1 trafficking).
  • Localization/lateralization: Systemic and bilateral (lymphadenopathy, cytopenias); no characteristic lateralization.

8. Temporal Development

  • Onset: Childhood-onset, typically early (some as young as infancy/toddlerhood; the new Ashari case was 5 years old). Onset pattern is chronic with acute infectious/autoimmune exacerbations.
  • Progression: Progressive and episodic; lymphoproliferation may precede overt lymphoma. Vasculopathy and AIHA can be rapidly life-threatening.
  • Disease course: Chronic, lifelong without curative HSCT.
  • Critical periods / windows for intervention: Early diagnosis before EBV-driven lymphoma or fatal autoimmune complications; HSCT before end-organ damage offers the best outcome.

9. Inheritance and Population

  • Epidemiology: Ultra-rare — approximately 15 reported patients worldwide (Finding 4). No reliable prevalence/incidence figures exist; effectively <1 per 1,000,000.
  • Inheritance: Autosomal recessive (biallelic LOF).
  • Penetrance / expressivity: Appears high penetrance for immunodeficiency/lymphoproliferation in biallelic-null individuals, with variable expressivity for autoimmunity, lymphoma type, and vasculopathy.
  • Consanguinity: Major contributor; most reported families are consanguineous with homozygous variants.
  • Founder effects / carrier frequency: No established founder alleles; carrier frequency not defined but presumed very low (rare private alleles).
  • Population demographics: Cases reported from consanguineous populations (e.g., Middle Eastern, including Iranian and Turkish cohorts — PMID: 38644452, PMID: 38683392); no strong sex bias established. Common (non-causal) RASGRP1 autoimmunity alleles show population-specific frequencies (East Asian SLE, European RA — Finding 6).

10. Diagnostics

  • Laboratory / immunologic tests: Lymphocyte subset quantification (variable T/B/NK abnormalities; some patients absent B cells/hypogammaglobulinemia — PMID: 38683392); functional assays — reduced TCR-induced ERK phosphorylation, reduced RAS-GTP loading, impaired T/B proliferation, and defective NK cytotoxicity (Findings 1, 3). EBV viral-load monitoring is essential.
  • Biomarkers: No specific circulating biomarker; functional signaling defects and EBV load serve as surrogate markers.
  • Imaging: CT/PET for lymphadenopathy/lymphoma staging; vascular imaging for vasculopathy.
  • Biopsy/pathology: Lymph-node/tissue biopsy to distinguish reactive lymphoproliferation from lymphoma (Hodgkin/non-Hodgkin); renal biopsy where nephrotic syndrome occurs.
  • Genetic testing (recommended, definitive): Whole-exome sequencing (WES) or whole-genome sequencing (WGS), or targeted IEI/PIRD next-generation-sequencing panels including RASGRP1 (e.g., Ion AmpliSeq Primary Immune Deficiency panel — PMID: 38644452); confirm with Sanger and segregation. Homozygosity mapping is useful in consanguineous families.
  • Clinical criteria / differential diagnosis: Consider within ALPS-like / PIRD and EBV-susceptibility IEIs; differentials include XLP1 (SH2D1A), XLP2 (XIAP), ITK, MAGT1, CD27/CD70, CTPS1, CORO1A deficiencies (PMID: 34447369, PMID: 36209991). Genetic testing distinguishes them.
  • Screening: Cascade genetic testing in families; carrier testing for at-risk relatives; EBV surveillance in known-affected individuals.

11. Outcome / Prognosis

  • Survival/mortality: No formal survival curves exist for this ultra-rare disorder. Prognosis is guarded: conservative management carries high mortality (Finding 4). Fatal outcomes reported from lymphoma, severe infection, autoimmune hemolytic anemia, and vasculopathy. As broader context, lymphoma arising on a background of primary immunodeficiency has markedly worse survival than in immunocompetent patients (5-yr OS 41% vs 80% in a PID-malignancy cohort — PMID: 35282762).
  • Morbidity/function: High — recurrent infection, chronic immunosuppression, chemotherapy, transplant-related morbidity.
  • Complications: EBV lymphoma, autoimmune cytopenias, vasculopathy, nephrotic syndrome, infection.
  • Recovery potential: HSCT can be curative (Finding 4); without it, chronic and often fatal.
  • Prognostic factors: Early diagnosis, EBV control, absence of established lymphoma/vasculopathy at transplant, and successful HSCT engraftment.

12. Treatment

Modality Intervention Evidence / rationale NCIT (suggested)
Curative Allogeneic HSCT Only curative therapy; corrects the hematopoietic-restricted defect (Finding 4) NCIT:C15431 (Hematopoietic Stem Cell Transplantation)
Mechanism-based experimental Lenalidomide Restores RhoA activity, reverses migration/activation defects in patient cells (Finding 3) NCIT:C1873 (Lenalidomide)
Anti-B-cell / lymphoma Rituximab, chemotherapy Controls EBV-driven B-cell proliferation/lymphoma NCIT:C1702 (Rituximab)
Immune dysregulation Immunosuppression / immunomodulation Manages autoimmunity (cytopenias, vasculopathy) NCIT:C15329 (Immunosuppressive Therapy)
Supportive IVIG replacement, antimicrobial prophylaxis For hypogammaglobulinemia and infection prevention NCIT:C579 (Immunoglobulin Therapy)
Surveillance EBV viral-load monitoring Early detection of lymphoproliferation —
  • Pharmacogenomics: Not established for IMD64.
  • Gene/cell/RNA therapies: No approved gene therapy; RASGRP1 is a rational future gene-correction/HSC gene-therapy target given the hematopoietic-restricted phenotype, but this remains preclinical/theoretical.
  • Treatment strategy: Genotype-driven — confirm biallelic RASGRP1 LOF, control EBV/lymphoma, manage autoimmunity, and proceed to HSCT as definitive therapy.

13. Prevention

  • Primary prevention: Not possible for the genetic defect. Genetic counseling and, in consanguineous families, awareness of recessive risk. Prenatal/preimplantation genetic testing for known familial variants.
  • Secondary prevention: Early molecular diagnosis (WES/panel), cascade testing, and EBV surveillance to catch lymphoproliferation early.
  • Tertiary prevention: Infection prophylaxis (antimicrobials, IVIG), vaccination per IEI guidelines (avoid live vaccines where cellular immunity is compromised), and timely HSCT to prevent lethal complications.
  • Counseling: Autosomal-recessive recurrence risk 25% for future offspring of carrier parents; offer carrier testing and reproductive options.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: RASGRP1 is conserved. Mouse Rasgrp1 (Mus musculus, NCBI Taxon 10090; NCBI Gene 19419) is the principal ortholog studied.
  • Natural disease in animals: No well-characterized spontaneous RASGRP1-deficiency disease reported in companion animals or wildlife (no OMIA entry noted).
  • Comparative biology: The Ras–ERK requirement for thymocyte positive selection and β-selection is evolutionarily conserved, validated extensively in mouse (see Section 15). Human and mouse share the core TCR→RASGRP1→ERK developmental mechanism.
  • Zoonotic potential: Not applicable (non-transmissible genetic disorder).

15. Model Organisms

  • Primary model: Mouse (Rasgrp1) knockout and knock-in models, which recapitulate key mechanistic features:
  • Positive selection defect: RasGRP1 is the dominant RasGEF required at the TCR checkpoint; its deletion efficiently blocks positive selection (PMID: 22586275).
  • β-selection / DN3 block & CXCR4-ERK link: RasGRP1-KO thymi show a partial DN3 developmental block and reduced proliferation; RasGRP1 is required for ERK activation downstream of CXCR4 (PMID: 23308188).
  • Tail-domain knock-in: Deletion of the unique C-terminal tail impairs membrane trafficking and ERK activation and drives CD4⁺ expansion/autoantibodies with age (PMID: 22719950) — modeling the autoimmunity axis.
  • γδ T cells & agonist selection: RasGRP1 is required for γδ T-cell proliferation/IL-17 and for agonist selection of TCRαβ lineages (PMID: 22623331, PMID: 28652304).
  • Cellular / in vitro models: Jurkat T-leukemia cells used to demonstrate perturbed ERK1/2 and reduced RAS-GTPase activity from patient variants (PMID: 30030704); patient-derived primary lymphocytes/NK cells for functional rescue (WT re-expression, lenalidomide) (PMID: 27776107).
  • Phenotype recapitulation & limitations: Mouse models faithfully reproduce the T-cell developmental and ERK-signaling defects and the autoimmunity predisposition, but do not recapitulate EBV-driven lymphoproliferation (EBV is human-restricted), a central feature of the human disease — the key limitation for modeling IMD64.
  • Resources: MGI (Rasgrp1), IMPC/KOMP for engineered alleles; Cellosaurus for Jurkat.

Mechanistic Model / Interpretation

RASGRP1 is the molecular switch that translates antigen-receptor engagement into RAS-ERK activation in lymphocytes. Structural work (Finding 5) shows it is normally autoinhibited — catalytic site occluded, membrane surface buried in a dimer — until Ca²⁺ and DAG relieve autoinhibition and recruit it to the membrane to load RAS-GTP. Biallelic LOF mutations (Finding 1) destroy this switch. The consequences fan out along two arms: (i) a RAS-ERK arm that governs thymocyte selection and lymphocyte proliferation/activation, and (ii) a cytoskeletal arm via DYNLL1/RhoA that governs lymphocyte motility and NK immune-synapse/granule dynamics (Finding 3). Failure of both arms yields a combined immunodeficiency whose most dangerous manifestation is loss of CD8⁺/NK control over EBV-infected B cells (Finding 2), driving lymphoproliferation and lymphoma; concurrently, disrupted tolerance produces autoimmunity, including cytopenias and an emerging fatal vasculopathy (Finding 4).

The allelic spectrum (Finding 6) ties the rare and common ends together: partial perturbation of RASGRP1 dosage predisposes to polygenic autoimmunity (SLE, RA, thyroiditis, IgAN), while complete biallelic loss produces monogenic IMD64. This dosage sensitivity marks RASGRP1 as a rheostat of immune homeostasis.

Evidence Base

PMID Title (abbrev.) Role in this report
27776107 RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics Landmark: causal gene, ERK rescue, DYNLL1/RhoA, lenalidomide (Findings 1, 3)
30030704 Novel Mutations in RASGRP1... EBV-Induced Lymphoma Independent LOF confirmation; EBV malignancy (Findings 1, 2)
37898412 Novel homozygous RASGRP1 mutation... EBV-induced B cell proliferation Direct EBV-control failure (Finding 2)
31402499 Signaling pathways in T-cell immunity against EBV Mechanistic placement with MAGT1/ITK (Finding 2)
42253627 RASGRP1 Deficiency... Severe Vasculopathy and Fatal AIHA Cohort quantification, vasculopathy, HSCT (Finding 4)
23908768 Structural analysis of autoinhibition in RasGRP1 Autoinhibition/activation structure (Finding 5)
26808113 SLE risk variants, Asian ancestry RASGRP1 as SLE locus (Finding 6)
26939566 RA variants, European RASGRP1 as RA locus (Finding 6)
27268232 TPOAb variants, Hashimoto's RASGRP1 autoimmune thyroid locus (Finding 6)
27804980 RGS1/RASGRP1 in IgA nephropathy RASGRP1 autoimmune renal locus (Finding 6)
22586275, 23308188, 22719950, 22623331, 28652304 Mouse Rasgrp1 studies Model-organism validation (Section 15)
34447369, 36209991, 38644452, 38683392, 39752212, 35282762 PIRD/ALPS-like, panels, phenotypes Differential diagnosis, diagnostics, prognosis

Limitations and Knowledge Gaps

  • Very small evidence base (~15 patients): Frequency estimates (100% infections, 87% lymphoproliferation) come from aggregated case reports and are subject to ascertainment/publication bias.
  • No formal epidemiology: True prevalence, incidence, penetrance, sex ratio, and survival statistics are unknown.
  • No large omics datasets: Transcriptomic/proteomic/metabolomic disease signatures and single-cell studies are lacking.
  • EBV cannot be modeled in mouse: The central lymphoproliferative phenotype is human-restricted; humanized models are needed.
  • Vasculopathy mechanism undefined: The emerging fatal vasculopathy is described phenomenologically but not mechanistically dissected.
  • Therapeutics largely anecdotal: Lenalidomide efficacy is based on ex-vivo/limited clinical data; HSCT outcomes lack systematic cohort analysis.
  • Ontology/identifier gaps: MONDO/OMIM are established, but Orphanet/ICD-11/MeSH mappings are imprecise for this recently defined entity.

Proposed Follow-up Experiments / Actions

  1. Establish an international IMD64 patient registry to obtain robust frequency, penetrance, HSCT-outcome, and survival data.
  2. Systematic HSCT outcome analysis — timing, conditioning, and pre-transplant lymphoma/vasculopathy status as prognostic factors.
  3. Prospective evaluation of lenalidomide (and other RhoA-restoring agents) as bridging therapy, with standardized functional endpoints (RhoA activity, migration, NK cytotoxicity).
  4. Humanized/EBV-permissive models (e.g., RASGRP1-null humanized mice, patient-iPSC-derived lymphoid organoids) to model EBV lymphoproliferation and test gene correction.
  5. Mechanistic study of the vasculopathy — vessel-wall immunopathology, autoantibody characterization, and cytokine profiling.
  6. Autologous HSC gene therapy/gene editing feasibility studies for RASGRP1 correction, given the hematopoietic-restricted phenotype.
  7. Single-cell multi-omics of patient lymphoid compartments to map cell-type-specific consequences of RAS-ERK collapse and identify biomarkers of lymphoma risk.
  8. Deep-phenotyping of EBV surveillance protocols to define optimal viral-load thresholds triggering pre-emptive rituximab.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 23
Resolved 23
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 23
On topic 10
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 40
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 26
Terms named correctly 16
Terms named as a different term 4
Terms whose name is worth a second look 6

Terms the report names something else

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

  • HP:0012177 (1 mention) - the report calls it "Decreased proportion of NK cells"; HP calls it Abnormal natural killer cell physiology
  • GO:0005768 (1 mention) - the report calls it "endosome; RasGRP1 trafficking"; GO calls it endosome
  • NCIT:C15329 (1 mention) - the report calls it "Immunosuppressive Therapy"; NCIT calls it Surgical Procedure
  • NCIT:C579 (1 mention) - the report calls it "Immunoglobulin Therapy"; NCIT calls it Inorganic Chemical

Terms whose name is worth a second look

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

  • GO:0002323 (1 mention) - the report calls it "natural killer cell activation"; GO calls it natural killer cell activation involved in immune response, and lists "natural killer cell activation during immune response" among its other names
  • CL:0000625 (1 mention) - the report calls it "CD8⁺ T cell"; CL calls it CD8-positive, alpha-beta T cell
  • CL:0000624 (1 mention) - the report calls it "CD4⁺ T cell"; CL calls it CD4-positive, alpha-beta T cell
  • GO:0005886 (1 mention) - the report calls it "plasma membrane; site of RAS activation"; GO calls it plasma membrane, and lists "plasma membrane lipid bilayer" among its other names
  • GO:0005856 (1 mention) - the report calls it "cytoskeleton; DYNLL1/RhoA arm"; GO calls it cytoskeleton
  • NCIT:C1873 (1 mention) - the report calls it "Lenalidomide"; NCIT calls it Apomine