Immunodeficiency 85 and Autoimmunity (IMD85): Comprehensive Research Report

1. Disease Information

Overview: Immunodeficiency 85 and autoimmunity (IMD85) is an ultra-rare, autosomal dominant primary immunodeficiency/immune dysregulation disorder caused by a heterozygous missense mutation in TOM1 (Target Of Myb1 Membrane Trafficking Protein). It is characterized by early-onset (first decade of life) atopic eczema and recurrent respiratory infections, progressing to multi-organ autoimmunity (autoimmune enteropathy, oligoarthritis, interstitial pneumonitis), hypogammaglobulinemia, and combined T- and B-cell dysfunction. To date it has been described in a single two-generation family (mother and son) (OMIM 619510; Keskitalo et al. 2019, PMID:31263572).

Key Identifiers: - OMIM: 619510 (IMMUNODEFICIENCY 85 AND AUTOIMMUNITY; IMD85) - Causal gene OMIM: 604700 (TARGET OF MYB1 MEMBRANE TRAFFICKING PROTEIN; TOM1) - HGNC: TOM1, HGNC:11982 - Ensembl: ENSG00000100284 (chr22:35,299,275–35,347,995, GRCh38) - Chromosome location: 22q12.3 - Mondo: Not independently confirmed to have a distinct MONDO ID in this search pass; would map via OMIM:619510 cross-reference — verify with runoak -i sqlite:obo:mondo before curating a disease_term binding. - Orphanet: No dedicated Orphanet entry was found distinct from the OMIM/gene page (orpha.net/en/disease/gene/TOM1 lists the gene-disease association). - Synonyms:* IMD85; "TOM1 deficiency"; "Dominant TOM1-associated combined immunodeficiency and autoimmunity"

Source basis: This entire disease concept derives from a single aggregated case report of one family (2 affected individuals across 2 generations) plus a 2025 follow-up mechanistic study on cells from the same two patients — not from population-level EHR or registry data. All prevalence/frequency statements below should be read as "reported in 1 family" rather than population estimates.

2. Etiology

Disease Causal Factor: Heterozygous, autosomal dominant, gain-of-interference (likely dominant-negative) missense mutation in TOM1.

Genetic risk factor (causal variant): - Variant: c.920G>A, p.Gly307Asp (p.G307D) — genomic position chr22:35,728,994 G>A (note: this coordinate as reported may reflect an older genome build; cross-check against current GRCh38 TOM1 coordinates during curation) - Located in the GAT (GGA and TOM1) domain of TOM1, which mediates ubiquitin-binding and TOLLIP interaction - SIFT: "deleterious"; PolyPhen-2: "probably damaging" - Affects a conserved residue - Segregates with disease in a mother (Patient 1, II.2) and her son (Patient 2, III.1) — autosomal dominant transmission, heterozygous in both.

No environmental, infectious, or additional genetic risk/protective factors have been reported for this ultra-rare monogenic disorder; EBV viremia is a consequence of the immunodeficiency (impaired immune control), not a causal trigger. The authors explicitly note: "phenotypic heterogeneity is common in monogenic immune diseases and points to additional genetic modifiers" (PMID:31263572) — i.e., they flag but do not identify specific modifier loci, as onset age and severity differed markedly between mother and son.

Gene-Environment Interactions: None reported/studied.

3. Phenotypes

Onset, in order of typical appearance, drawn from the two reported cases (mother onset in early teens; son onset at 6 months of age — illustrating that onset is highly variable even within one family):

Severity/progression: Highly variable between the two patients despite an identical variant — the mother's course was comparatively indolent (survives to at least age 32 at publication), while the son had a fulminant infantile-onset multi-organ course, received an allogeneic HSCT around age 9, rejected the graft within 6 months, and died approximately one year post-transplant from progressive pulmonary fibrosis. This intrafamilial variability is explicitly discussed by the authors as evidence for unidentified modifiers.

Quality of life impact: Not formally measured (no EQ-5D/SF-36 data); qualitatively, the son's disease was fatal, and the mother required chronic immunosuppression (prednisolone, methotrexate) and immunoglobulin replacement (subcutaneous, after IVIG was discontinued for adverse effects).

4. Genetic/Molecular Information

Causal Gene: TOM1 (HGNC:11982; OMIM *604700), located 22q12.3.

Pathogenic Variant: - c.920G>A; p.(Gly307Asp), heterozygous, missense - ACMG classification not explicitly stated in the source, but functionally characterized as pathogenic via multiple orthogonal assays (interactome, autophagy, apoptosis, signaling) - Not present in population databases at appreciable frequency (implied by rarity; not explicitly quoted with a gnomAD frequency in the sources retrieved) - Functional consequence: dominant-negative / loss-of-interaction. The mutant protein is expressed at normal levels (confirmed by Western blot) but is functionally crippled at the protein-interaction level — this is not a simple loss-of-function null allele, since TOM1 is expressed and heterozygosity with presumably one WT allele still yields dominant disease, consistent with dominant-negative interference or haploinsufficiency-plus-modifier effects.

Modifier Genes: None identified; authors explicitly call for additional families to establish modifiers explaining intrafamilial severity variation.

Somatic vs. Germline: Germline (heritable, present in both mother and son).

Chromosomal Abnormalities: None — this is a single-nucleotide missense variant, not a structural rearrangement.

Suggested annotation: functional_impact_category: DOMINANT_NEGATIVE (per dismech's GeneticContext guidance) is the best-supported categorical fit, since the mutant protein is expressed normally but interferes with a specific protein-protein interaction (TOM1–TOLLIP) required for normal pathway function.

5. Environmental Information

No environmental, lifestyle, or infectious triggering factors are described as causal. EBV is present as an opportunistic/uncontrolled infection secondary to the immunodeficiency (i.e., a consequence, not a cause) — this should be modeled as a phenotype/complication, not an environmental entry with a TRIGGERS edge.

6. Mechanism / Pathophysiology

Molecular Function of TOM1 (Wild-Type)

TOM1 is a multimodular endosomal adaptor protein containing VHS and GAT domains. It binds ubiquitinated cargo and, via its GAT domain, interacts with TOLLIP (Toll-interacting protein), clathrin, and myosin VI to regulate: - Endosomal sorting/trafficking of ubiquitinated cargo (ESCRT-associated pathway) - Autophagosome maturation and autophagosome–lysosome fusion - Negative regulation of Toll-like receptor (TLR)/IL-1 receptor (PAMP) signaling - Receptor recycling

Causal Chain (Molecular → Cellular → Clinical)

1. Molecular lesion: p.G307D destabilizes the GAT domain's interaction surface.
2. AP-MS interactome: mutant TOM1 shows markedly reduced binding to ubiquitin C (2.8% vs. 5.7% in WT) and TOLLIP (11.2% vs. 22.0% in WT).

3. Follow-up mechanistic study (PMID:40936361, 2025) refines this: the mutant fails to properly release TOLLIP from PI3P-bound endosomal membranes, "impairing cargo trafficking commitment," and specifically delays autophagosome clearance rather than blocking autophagosome formation — LC3B–LAMP1 colocalization (a marker of autophagosome-lysosome fusion) was reduced to 54% of control.

4. Cellular consequence — impaired autophagy: Patient lymphocytes show decreased LC3 staining (low autophagosome count); rapamycin (an autophagy inducer) fails to rescue autophagosome number in patient cells, indicating a block downstream of induction (at the fusion/maturation step).

5. Cellular consequence — dysregulated signaling:

6. Baseline: ERK1/2 phosphorylation significantly downregulated; STAT1 and STAT5 phosphorylation impaired (p38, S6 relatively preserved) — quote: "ERK1/2 phosphorylation was significantly downregulated in both patients...indicating dysfunctional MAPK signaling."

7. Under acute stimulation (LPS/IL-1β), the 2025 follow-up found the opposite direction — more robust ERK1/2 phosphorylation after LPS/IL-1β stimulation in patient fibroblasts than controls — consistent with loss of the normal negative-regulatory ("braking") function TOM1/TOLLIP exert over innate immune signaling, i.e., a switch from tonic under-signaling to stimulus-triggered over-signaling. Curators should note this apparent directionality difference between the 2019 and 2025 papers reflects different cell types/conditions (baseline vs. acute PAMP stimulation) rather than a contradiction, and both should be captured as distinct pathophysiology nodes.

8. Cellular consequence — enhanced apoptosis: PBMCs from both patients show elevated apoptotic/dead-cell fractions (~50% of the son's lymphocytes showed an apoptotic phenotype).

9. Immune cell consequences:

10. Impaired T-cell maturation: increased naive, decreased effector memory (TEM) and TEMRA subsets; poor IFN-γ and IL-17 secretion upon stimulation.
11. Regulatory T cells: normal numbers but impaired suppressive function (notably in the son).
12. B cells: severely reduced switched memory B cells (0% in both, vs. 6.5–29.2% reference) and hypogammaglobulinemia (IgG, IgA, IgM all low).

13. NK cells and plasmacytoid/monocytoid dendritic cells: markedly reduced in both patients.

14. Clinical manifestation: The combination of (a) impaired autophagy/autophagosome clearance, (b) dysregulated (both tonic-low and stimulus-triggered-high) MAPK/JAK-STAT signaling, (c) enhanced lymphocyte apoptosis, and (d) broad lymphoid subset abnormalities (T, B, NK, DC) together produce a combined immunodeficiency with concurrent multi-organ autoimmunity — impaired pathogen clearance/antibody production coexisting with loss of normal negative regulation of inflammatory signaling and defective Treg function, permitting autoimmune tissue damage (skin, gut, lung, joints).

Suggested Ontology Terms

• GO Biological Process: GO:0016236 (macroautophagy), GO:0000045 (autophagosome assembly), GO:1901097 (negative regulation of autophagosome maturation — for the mutant defect), GO:0034249 (negative regulation of cellular amide metabolic process; consider more specific TLR-signaling terms), GO:0034141 (positive regulation of toll-like receptor 3 signaling pathway) as a starting point for TLR/PAMP regulation, GO:0006915 (apoptotic process), GO:0007265 (Ras protein signal transduction)/ERK cascade terms (GO:0070371, ERK1 and ERK2 cascade), GO:0006355/JAK-STAT terms
• GO Molecular Function: GO:0043130 (ubiquitin binding)
• GO Cellular Component: GO:0005768 (endosome), GO:0005771 (multivesicular body), GO:0000421 (autophagosome membrane)
• Cell types (CL): CL:0000542 (lymphocyte), CL:0000236 (B cell), CL:0000818 (switched memory B cell), CL:0000625 (CD8+ T cell), CL:0000895 (naive thymus-derived CD4-positive T cell), CL:0000815 (regulatory T cell), CL:0000623 (natural killer cell), CL:0000784 (plasmacytoid dendritic cell)
• CHEBI: N/A (no small-molecule mechanism per se, though rapamycin/tacrolimus are relevant to treatment)

7. Anatomical Structures Affected

• Primary organ systems: Skin (eczema, psoriasis), gastrointestinal tract (autoimmune enteropathy), respiratory system (lung — interstitial pneumonitis/fibrosis; also recurrent infections), musculoskeletal (joints — oligoarthritis), immune system (lymphoid compartment broadly)
• UBERON suggestions: UBERON:0002097 (skin of body), UBERON:0002108 (small intestine), UBERON:0002048 (lung), UBERON:0000982 (joint), UBERON:0002193 (hemolymphoid system)
• Tissue/cell level: Lymphocytes (T, B, NK), dendritic cells, epithelial cells of gut and lung
• Subcellular level (GO CC): Early/late endosome, autophagosome, lysosome — the primary subcellular site of the molecular defect
• Laterality: Not applicable (systemic/multi-organ disease, not lateralized)

8. Temporal Development

• Onset: Highly variable within the single reported family — infantile (6 months, son) to early-teen (mother). No population-level onset statistics exist given the single-family basis.
• Onset pattern: Insidious/progressive in both cases, punctuated by acute complications (e.g., graft rejection in the son).
• Progression: Progressive and severe in the son (death ~1 year post-HSCT from progressive pulmonary fibrosis); more indolent/chronic in the mother, who was alive and on chronic immunosuppression/Ig replacement at age 32 at time of publication.
• Disease course pattern: Chronic, progressive, with episodic flares (e.g., eczema/respiratory flares triggered by an mTOR-inhibitor trial in the son).
• Remission: Temporary — HSCT produced "temporary resolution of autoimmune symptoms" in the son, but this was lost within 6 months due to graft rejection, after which "the disease returned."
• Critical periods: Infancy appears to represent a high-risk window for the most severe, multi-organ, rapidly progressive presentation, based on the son's course.

9. Inheritance and Population

• Epidemiology: Reported in exactly one family (2 affected individuals) worldwide as of the literature retrieved — true prevalence/incidence cannot be estimated; this is an ultra-rare "N-of-1 family" monogenic disease.
• Inheritance pattern: Autosomal dominant (heterozygous mutation, vertical transmission mother→son).
• Penetrance: Appears complete in this family (both carriers affected) but expressivity is markedly variable (see below).
• Expressivity: Highly variable — same p.G307D variant produced a comparatively milder, later-onset course in the mother versus a severe, fatal, infantile-onset course in the son. Authors explicitly attribute this to likely unidentified genetic modifiers.
• Genetic anticipation: Potentially suggested by the pattern (later/milder in mother vs. earlier/more severe in son), but this cannot be distinguished from stochastic/modifier effects with an n=2 pedigree; not formally established.
• Germline mosaicism, founder effects, consanguinity, carrier frequency: Not applicable/not reported — this is a de novo-type autosomal dominant single-family report, not a population-level recessive or founder disease.
• Population demographics: Not established (single Northern European-ancestry family per source institution context — precise ancestry not stated in retrieved excerpts). Sex ratio: 1 female (mother), 1 male (son) — no inference possible from n=2.

10. Diagnostics

Laboratory/Immunophenotyping (as performed in the index family): - Complete blood count with lymphocyte subsets (flow cytometry): CD19+ B cells, switched memory B cells, CD4+/CD8+ T cells, NK cells, plasmacytoid and monocytoid dendritic cells - Quantitative immunoglobulins (IgG, IgA, IgM) — both patients markedly hypogammaglobulinemic - T-cell functional assays: cytokine secretion (IFN-γ, IL-17) upon stimulation; Treg suppression assays - Phospho-flow cytometry for STAT1, STAT5, ERK1/2, p38, S6 signaling - LC3 immunostaining (autophagosome quantification) in lymphocytes/fibroblasts - Apoptosis assays (annexin V/PI or equivalent) on PBMCs

Genetic Testing: - Whole-exome or targeted sequencing identified the heterozygous TOM1 c.920G>A (p.G307D) variant; Sanger confirmation and familial segregation testing would be standard practice for a suspected combined immunodeficiency with autoimmunity phenotype. - Given the phenotypic overlap with other combined immunodeficiency/immune dysregulation syndromes (e.g., CVID, ALPS, IPEX-like disorders), a primary immunodeficiency/monogenic IBD gene panel is the practical diagnostic entry point — TOM1 is listed on the PanelApp (Genomics England) "Primary immunodeficiency or monogenic inflammatory bowel disease" panel and the PanelApp Australia "Autoinflammatory Disorders" panel.

Functional/Research-Level Confirmatory Testing (not yet clinical-grade): - AP-MS interactome analysis (TOM1–TOLLIP, TOM1–ubiquitin binding) - LC3B–LAMP1 colocalization imaging (autophagosome-lysosome fusion assay) - Response of ERK1/2 phosphorylation to LPS/IL-1β stimulation in patient-derived fibroblasts

Clinical Criteria: No formal consensus diagnostic criteria exist (single-family disease); diagnosis is genotype-driven with immunophenotypic and functional corroboration.

Differential Diagnosis: Should include other genetic causes of combined immunodeficiency with autoimmune enteropathy (e.g., IPEX/FOXP3, LRBA deficiency, CTLA4 haploinsufficiency, STAT3 GOF), CVID with autoimmune features, and other autophagy-pathway immune dysregulation disorders. Notably, the 2019 paper specifically tested and found normal CTLA4, IL-1R, and IL-6R expression, ruling out a primary receptor-expression defect and supporting a trafficking/autophagy-centric mechanism instead.

Screening: No population or newborn screening applicable (ultra-rare, private family variant).

11. Outcome/Prognosis

• Survival/mortality: The son (severe, infantile-onset presentation) died approximately 1 year after allogeneic HSCT, from progressive pulmonary fibrosis following graft rejection — total lifespan to age ~10. The mother remained alive at age 32 at the time of reporting, managed on chronic immunosuppression and immunoglobulin replacement.
• Morbidity: Substantial — chronic autoimmune enteropathy, growth failure, recurrent infections, interstitial lung disease, and treatment-refractory skin disease.
• Complications: EBV viremia, treatment-resistant psoriasis, graft rejection post-HSCT, progressive pulmonary fibrosis (fatal in the reported case).
• Recovery potential: HSCT achieved only temporary resolution of autoimmune symptoms before graft rejection at 6 months; this single data point suggests HSCT may not be reliably curative for this genotype, though n=1 limits generalization.
• Prognostic factors: Age of onset (infantile vs. teenage) appeared associated with severity in this family, though this cannot be statistically validated given n=2.

12. Treatment

Pharmacotherapy used in the reported family (NCIT terms suggested): - Prednisolone (oral corticosteroid) — mother; ongoing — NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI (prednisolone) - Methotrexate — both patients — NCIT:C15986 - Tacrolimus (oral) — son — NCIT:C15986 - Everolimus (mTOR inhibitor) — trialed in the son specifically to target autoimmunity (rationale: mTOR/autophagy pathway involvement) but caused adverse flares of eczema and respiratory distress — an important negative treatment-response finding worth capturing as a NO_EVIDENCE/adverse-effect annotation rather than a recommended therapy - Intravenous immunoglobulin (IVIG) — mother; discontinued due to adverse effects — NCIT (immunoglobulin replacement therapy term) - Subcutaneous immunoglobulin replacement — both patients, ongoing — better tolerated than IVIG

Cell therapy: - Allogeneic hematopoietic stem cell transplantation (HSCT) — son, at approximately age 9 — NCIT:C15431 (Hematopoietic Cell Transplantation) → therapeutic_modality: CELL_THERAPY. Achieved temporary resolution of autoimmune symptoms; graft rejected within 6 months; disease recurred; patient died ~1 year post-transplant of progressive pulmonary fibrosis.

Treatment strategy/algorithm: No established treatment algorithm exists given the single-family basis; management to date has been empirically immunosuppressive/replacement-based (corticosteroids, methotrexate, calcineurin inhibitor, Ig replacement) with HSCT attempted as a potentially curative but ultimately unsuccessful option in the most severe case. The failed everolimus trial is a notable cautionary data point suggesting mTOR inhibition is not an effective/safe strategy despite the pathway's mechanistic proximity (autophagy regulation).

Experimental treatments: None in formal clinical trials (no NCT identifiers found; this is far too rare for a registered trial).

13. Prevention

No primary, secondary, or tertiary prevention strategies are described or applicable — this is a private autosomal dominant germline variant in a single known family. The only relevant preventive consideration would be genetic counseling for at-risk relatives (NCIT:C15240, Genetic Counseling) and prenatal/preimplantation testing if desired by family members, given the 50% transmission risk from an affected parent, though none of this is explicitly documented in the retrieved sources.

14. Other Species / Natural Disease

• Taxonomy: No naturally occurring TOM1-associated disease has been reported in non-human species in the sources retrieved.
• Orthologous gene: Tom1 — mouse ortholog MGI:1338026 (chromosome 8C1); zebrafish ortholog tom1 (ZFIN ZDB-GENE-060721-1). TOM1-family genes are evolutionarily conserved (TOM1, TOM1L1, TOM1L2 paralogs in humans; original TOM1 gene family first mapped via similarity to endosomal proteins HGS and STAM, PMID:10329004).
• Comparative biology: No OMIA (Online Mendelian Inheritance in Animals) entry or veterinary case series identified. No evidence of naturally occurring veterinary TOM1-associated immunodeficiency.
• Transmission/zoonotic potential: Not applicable — this is a monogenic, non-infectious, non-transmissible-between-species disorder.

15. Model Organisms

• No animal (mouse, zebrafish) or invertebrate models of the specific p.G307D variant or of TOM1 loss-of-function immunodeficiency were identified in the literature retrieved. Both key papers (Keskitalo et al. 2019, PMID:31263572; the 2025 Disease Models & Mechanisms follow-up, PMID:40936361) explicitly used only human patient-derived material and cell-line systems — no animal models:
• Patient-derived primary cells: PBMCs and dermal fibroblasts from the two affected family members
• Cell lines: Flp-In T-REx 293 cells (inducible WT vs. G307D TOM1 overexpression for interactome studies), HeLa cells (immunofluorescence/localization), HEK293A cells, U2OS cells (localization studies in the 2025 paper)
• Techniques: AP-MS (affinity purification–mass spectrometry) interactome profiling, BioID proximity labeling, phospho-flow cytometry, LC3B/LAMP1 immunofluorescence colocalization
• Model limitations: As the field currently has no in vivo (mouse) model of TOM1 G307D or Tom1 knockout immune phenotype, all mechanistic claims rest on ex vivo human patient cells and heterologous overexpression systems — a notable gap for future work, and a HUMAN_MODEL_MISMATCH/KNOWLEDGE_GAP framing does not directly apply here since there is no model organism data to be mismatched against; rather this is an outright absence of an animal model, worth flagging as a knowledge gap for curation purposes (no in vivo confirmation of causality/mechanism exists beyond the patient-cell/cell-line data).
• Resources: MGI:1338026 (mouse Tom1), ZFIN ZDB-GENE-060721-1 (zebrafish tom1) exist as gene records but no disease-phenotype model entries were found associated with them in this search.

Summary of Key Citations

Curator's note on evidence discipline: Given the disease rests on a single published family, every evidence item added to a kb/disorders/ entry should cite PMID:31263572 (primary) and/or PMID:40936361 (mechanistic follow-up) with exact abstract/text quotes verified via just fetch-reference — do not extrapolate population-level prevalence, penetrance, or treatment-efficacy claims beyond what these two case-based papers report, since no larger cohort, registry, or model-organism confirmation currently exists for IMD85.

Sources: - 619510 - IMMUNODEFICIENCY 85 AND AUTOIMMUNITY - OMIM - *604700 - TOM1 - OMIM - Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease - PMC (PMID:31263572) - Dominant TOM1 mutation... - npj Genomic Medicine - A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity - PMC (PMID:40936361) - A TOM1 variant impairs interaction with TOLLIP... - Disease Models & Mechanisms - TOM1 Gene - GeneCards - Gene: TOM1 (ENSG00000100284) - Ensembl - Gene: TOM1 (Primary immunodeficiency or monogenic inflammatory bowel disease) - PanelApp Genomics England - TOM1 (Autoinflammatory Disorders) - PanelApp Australia - TOM1 genes map to human chromosome 22q13.1... - PubMed (PMID:10329004) - Orphanet: TOM1-target of myb1 membrane trafficking protein - Tom1 MGI Mouse Gene Detail - MGI:1338026 - ZFIN Gene: tom1

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