Hatipoglu Immunodeficiency Syndrome

Mendelian MONDO:0957229 Pathograph 24 Show in embeddings browser inborn error of immunity inflammasomopathy bone marrow failure syndrome

Hatipoglu immunodeficiency syndrome is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function or hypomorphic variants in DPP9 (OMIM 620331). DPP9 is a cytosolic dipeptidyl peptidase whose job in innate immunity is restraint: it holds the two FIIND-domain inflammasome sensors, NLRP1 and CARD8, in a repressed ternary complex. When DPP9 is lost, that restraint is lifted and the sensors fire without any danger signal, so the disease is a derepression disorder rather than a sensor gain-of-function one. The clinical picture in the four children of the founding cohort was a triad of failure to thrive, skin manifestations and pancytopenia, together with susceptibility to bacterial and herpesviral infection. Three of the four needed haematopoietic stem cell transplantation for the marrow phenotype. Presentation is paediatric throughout - growth restriction from infancy, recurrent fever and transfusion-dependent anaemia - and the reported cohort is still small enough that patient counts, not frequencies, are the honest unit. Two things make the mechanism worth reading carefully. First, it splits by tissue and by species: NLRP1 drives the skin arm, demonstrated in patient keratinocytes, while the haematopoietic arm runs through CARD8, a gene that does not exist in the mouse - which is why Dpp9-mutant mice have normal haematopoiesis while the human disease is defined by marrow failure. Second, that split has a therapeutic consequence: IL-1 blockade addresses the NLRP1/IL-1 arm the animal models rescue, but the CARD8-driven pyroptosis of human stem cells was rescued by deleting CARD8 or CASP1 and not by deleting NLRP1.

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1
Inheritance
7
Pathophys.
25
Phenotypes
2
Gaps
24
Pathograph
1
Genes
4
Variants
3
Medical Actions
3
Models
3
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Every reported affected individual carries two damaged DPP9 alleles - homozygous stop-gained variants in the two consanguineous families, and a compound heterozygous missense/nonsense pair in the third. Parents and unaffected siblings were heterozygous or non-carriers. The twins of the 2025 case report were born to a non-consanguineous couple, so consanguinity enriches for the disease without being required for it.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"Each propositus was shown to segregate a homozygous germline stop-gained variant (c.331C>T; p.R111*) while available parents and siblings were either heterozygous or non-carrier consistent with Mendelian recessive inheritance."
Segregation in the Bedouin family, stated as establishing recessive inheritance.
PMID:41082409 SUPPORT Human Clinical
"Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder, characterized by cytopenias, recurrent infections, and failure to thrive associated with biallelic mutation in DPP9 gene."
An independent group naming the inheritance mode and the biallelic requirement.
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Discussions and Knowledge Gaps

2
Does any tractable model of this disease cover the skin and neurodevelopmental arms, given that the mouse lacks CARD8 and the humanized system contains only haematopoietic cells?
HUMAN MODEL MISMATCH hatis_model_coverage_gap
Attached to
pathophysiology#CARD8 Inflammasome Activation in Hematopoietic Progenitors phenotypes#Specific learning disability phenotypes#Delayed speech and language development phenotypes#Slurred speech phenotypes#Autism spectrum disorder
The two available in vivo models sit on opposite sides of the mechanism and neither spans it. Conventional Dpp9 mutant mice have the whole organism but no CARD8, so they cannot produce the marrow failure and cannot be used to ask what else the haematopoietic arm causes. The MISTRG6 system has human CARD8 but only in an engrafted haematopoietic compartment, so it cannot address skin, growth or neurodevelopment. The features with no model behind them are exactly the ones whose mechanism is unstated: learning disability and speech delay in three of four children, slurred speech and autism spectrum disorder in two each, and hemivertebrae in both children assessed, none of which has a demonstrated inflammasome route. The autism and the slurred speech are not scored in the same two children, so the cohort does not even offer a single neurodevelopmental phenotype to model. The mouse does reproduce runting and lung inflammation independently of NLRP1, which is a hint that DPP9 has inflammasome-independent roles - but it is a hint about stature, not about the neurodevelopmental findings.
What triggers CARD8 in DPP9-deficient human haematopoietic stem and progenitor cells?
KNOWLEDGE GAP hatis_card8_trigger_unknown
Attached to
pathophysiology#CARD8 Inflammasome Activation in Hematopoietic Progenitors
Loss of DPP9 removes a restraint; it does not by itself supply the signal a sensor responds to. The authors of the 2026 study say only that an undefined cellular stress during transplantation may be the trigger. Until that is identified it is not possible to say whether the disease is driven by chronic low-level firing or by episodic stress-driven bursts, and that distinction bears directly on whether a CARD8 or caspase-1 inhibitor would need to be given continuously or only around insults.
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Pathophysiology

7
Biallelic DPP9 Loss-of-Function Variants
The initiating lesion. Germline nonsense variants (p.R111*, p.S214*, p.Q851*) and one missense variant (p.G167S) affecting the substrate-binding site behave as knockout or hypomorphic alleles. The catalytic domain sits at the C-terminus, so the stop-gained alleles are expected to abolish enzymatic activity outright; no DPP9 protein at all was detectable in the fibroblasts of the p.Q851* homozygote.
DPP9 hgnc:18648 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DPP9 (hgnc:18648). hgnc:18648 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
DPP9 dipeptidyl peptidase activity GO:0008239 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DPP9 dipeptidyl peptidase activity, annotated with dipeptidyl-peptidase activity (GO:0008239). GO:0008239 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Proportionate short stature Drawn from the lesion rather than from the inflammasome node on purpose. In the mouse, runting persisted after NLRP1 deletion, so the growth phenotype is attributed to a DPP9 function that does not run through the inflammasome. Which function is not known, which is what the unknown-intermediates link type records.
Loss of DPP9 Restraint on FIIND Inflammasome Sensors The patient alleles are less able to hold NLRP1 in its inactive state, which is the function the downstream node loses.
Show evidence (2 references)
PMID:36112693 SUPPORT In Vitro
"these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1"
Classifies the allele series as hypomorphic or null, which is what the LOSS_OF_FUNCTION category on this node asserts.
PMID:36112693 SUPPORT Human Clinical
"The stop-gain mutations found in these 3 probands from Families 2 and 3 were expected to completely abolish the enzymatic activity of DPP9, since its catalytic domain is situated at the C-terminus."
The structural reason the nonsense alleles are nulls rather than partial-activity alleles.
Loss of DPP9 Restraint on FIIND Inflammasome Sensors
DPP9 normally sits in a ternary complex with full-length NLRP1 and the autoproteolytically released NLRP1 C-terminal UPA-CARD fragment, sequestering that fragment so it cannot oligomerise. CARD8 is held by an analogous, though not identical, DPP9 complex - the CARD8 C-terminus does not engage the DPP9 active site the way NLRP1's does, and DPP9's catalytic activity rather than its binding is what restrains CARD8. Losing DPP9 removes both restraints at once, which is why one enzyme deficiency produces two tissue-specific arms of disease.
DPP9 restraint of FIIND sensor inflammasome signalling GO:0141086 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DPP9 restraint of FIIND sensor inflammasome signalling, annotated with negative regulation of inflammasome-mediated signaling pathway (GO:0141086). GO:0141086 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
NLRP1 Inflammasome Activation in Keratinocytes
CARD8 Inflammasome Activation in Hematopoietic Progenitors The human haematopoietic arm. Deleting DPP9 in human CD34+ cells activates CARD8, and it is this branch rather than the NLRP1 branch that kills the cells.
Show evidence (3 references)
PMID:33731932 SUPPORT In Vitro
"The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT."
The structural basis of the repression this node loses. Note the source's own typography: it prints "NLRPT CT" where it means the NLRP1 C-terminal fragment, and the quote is reproduced as printed.
PMID:34019797 SUPPORT In Vitro
"Here, we report cryoelectron microscopy (cryo-EM) structures of CARD8 bound to DPP9, revealing a repressive ternary complex consisting of DPP9, full-length CARD8, and CARD8-CT."
The same repressive architecture for CARD8, which is the sensor behind the haematopoietic arm of this disease.
PMID:31525884 SUPPORT In Vitro
"Moreover, wild-type, but not catalytically inactive mutant, DPP9 rescues CARD8-mediated cell death in DPP9 knockout cells."
Establishes that it is DPP9 catalytic activity that restrains CARD8, which is why hypomorphic missense alleles and nulls converge on the same downstream node.
NLRP1 Inflammasome Activation in Keratinocytes
In skin, the liberated NLRP1 C-terminal fragment oligomerises, recruits ASC and pro-caspase-1, and fires without any exogenous trigger. Patient keratinocytes do this spontaneously in culture. The release is real but modest compared with pharmacological DPP8/DPP9 inhibition of control cells, because DPP8 remains intact in these patients and partially covers for the missing DPP9.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
interleukin-1 beta production GO:0032611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-1 beta production (GO:0032611). GO:0032611 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
IL-1-Driven Cutaneous and Systemic Inflammation
Show evidence (2 references)
PMID:36112693 SUPPORT In Vitro
"We demonstrated that the proband keratinocytes, as do keratinocytes from patients with gain-of-function NLRP1 mutations (5), spontaneously secreted active IL-1β and IL-18 into the media without any exogenous stimulus."
Direct human-cell demonstration of unprovoked inflammasome output, which is what this node claims.
PMID:36112693 SUPPORT In Vitro
"These data indicate that loss of DPP9 function in patient-derived cells could indeed be partially compensated by DPP8, accounting for their modest yet significant IL-1β release and cell death."
The DPP8 compensation that sets the magnitude of this node, and the reason the skin phenotype is milder than in NLRP1 gain-of-function disease.
CARD8 Inflammasome Activation in Hematopoietic Progenitors
The arm that defines the disease clinically, and the one no conventional mouse model could show. Human CD34+ haematopoietic stem and progenitor cells express CARD8 along with the full downstream apparatus. With DPP9 gone, CARD8 assembles and activates caspase-1. What triggers CARD8 in these cells is not established - the authors propose an as-yet-undefined cellular stress signal - so this node records de-repression, not a named trigger.
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
CARD8 inflammasome assembly GO:0140633 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased CARD8 inflammasome assembly, annotated with CARD8 inflammasome complex assembly (GO:0140633). GO:0140633 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells Deleting CASP1 rescues the cells, which is what makes the death caspase-1 dependent rather than merely caspase-1 associated.
Show evidence (2 references)
PMID:42741941 SUPPORT In Vitro
"Downstream effectors including CASP1 and GSDMD were similarly expressed, indicating that human HSPCs possess the complete molecular apparatus required for inflammasome-driven pyroptosis (Figure 4D)."
Establishes that the machinery this node needs is present in the cell type the node names.
PMID:42741941 SUPPORT Model Organism
"CARD8 may be triggered by a yet-to-be-defined cellular stress signal during transplantation of HSPCs and induce their pyroptosis in the absence of DPP9."
Records that the proximal trigger is unknown, which is why this node is written as de-repression rather than as a response to a named danger signal.
Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells
Active caspase-1 drives gasdermin-mediated membrane rupture and kills the cell. In the humanized-mouse system the loss is cell intrinsic: DPP9-deleted human HSPCs die whether or not unedited cells are present alongside them.
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
pyroptotic inflammatory response GO:0070269 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased pyroptotic inflammatory response (GO:0070269). GO:0070269 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
MISTRG6 humanized mice engrafted with CRISPR-edited human CD34+ HSPCs OTHER The system in which this node was demonstrated, in the human cell type the node names.
Downstream
Bone Marrow Stem and Progenitor Depletion
Show evidence (1 reference)
PMID:42741941 SUPPORT Model Organism
"The recapitulation of patient disease and the cell-intrinsic loss of stem cells suggest that the susceptibility to pyroptosis was a property of HSPCs rather than a consequence of transplantation models."
Supports the death being a property of the DPP9-deficient cell itself rather than of its environment.
Bone Marrow Stem and Progenitor Depletion
Loss of the stem and progenitor pool is what turns a molecular derepression into the marrow failure that drives the clinical course. It is the point at which the disease becomes transplant-dependent.
Animal models
Dpp9 S759A catalytically inactive knock-in mouse Mouse fails to recapitulate The mouse does not develop the cytopenia that defines the human disease.
Downstream
Pancytopenia
Anemia
Petechiae The thrombocytopenic limb of the pancytopenia, read through to the skin. The intermediate is megakaryocyte and platelet loss, which the cited sources report only as part of the pancytopenia rather than measuring separately, so the edge is an inference from the cytopenia and not a demonstrated platelet result.
Recurrent infections The infectious susceptibility is read here as downstream of marrow failure, which is how the 2026 study frames it, rather than as an independent lesion of immune function.
Show evidence (1 reference)
PMID:42741941 SUPPORT Model Organism
"Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic."
Both compartments lose cells, which is what this node asserts.
IL-1-Driven Cutaneous and Systemic Inflammation
Mature IL-1 beta released from unprovoked inflammasome activation is the effector of the non-haematological arm. The animal genetics point at IL-1 rather than IL-18: removing one copy of Il-1r rescued the mutant mouse, while removing Il-18 did not.
interleukin-1 beta production GO:0032611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-1 beta production (GO:0032611). GO:0032611 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Dpp9 S759A catalytically inactive knock-in mouse Mouse recapitulates The genetic rescue series is the strongest available evidence that IL-1 receptor signalling downstream of the NLRP1 inflammasome is the limiting effector of DPP9 deficiency in a whole animal.
dpp9 knockout zebrafish Zebrafish partially recapitulates Corroborates ASC dependence in a second species, which is why the inflammasome reading of DPP9 deficiency does not rest on mouse genetics alone.
Downstream
Periodic fever
Atopic dermatitis
Show evidence (2 references)
PMID:36112693 SUPPORT Model Organism
"The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice."
Identifies IL-1 receptor signalling, and not IL-18, as the limiting effector in the model - the reason this node is written around IL-1.
PMID:36112693 SUPPORT Model Organism
"These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling."
The summary claim for this node in the two animal models. It is a model-organism claim: the human haematopoietic arm turned out not to follow it.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hatipoglu Immunodeficiency Syndrome 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

25
Blood 3
Pancytopenia VERY_FREQUENT HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Pancytopenia | HP:0001876 | + | + | + | + | ✔ |"
The clinical summary table, scored positive in each of the four patients and marked as present in all cases.
PMID:36112693 SUPPORT Human Clinical
"Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants."
The cohort-level statement, naming pancytopenia as one of the defining features.
Anemia VERY_FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Anemia | HP:0001903 | + | + | + | + | ✔ |"
Positive in all four patients in the clinical summary table.
PMID:41082409 SUPPORT Human Clinical
"We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12..."
The independent case report, giving the age at presentation, the severity and the macrocytic, B12-unresponsive character of the anaemia.
Petechiae VERY_FREQUENT HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Petechiae | HP:0000967 | + | + | + | + | ✔ |"
Positive in all four patients in the clinical summary table.
Digestive 2
Poor feeding FREQUENT Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor feeding, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Poor feeding | HP:0011968 | + | + | − | − |"
Two of four positive in the clinical summary table.
Inguinal hernia FREQUENT HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Inguinal hernia | HP:0000776 | + | − | − | + |"
Two of four positive in the clinical summary table. The quoted identifier is the source's; the phenotype is bound to HP:0000023 for the reason given in the description.
Ear 1
Recurrent otitis media FREQUENT HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent otitis media (HP:0000403). HP:0000403 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Prone to acute otitis media | HP:0000403 | + | + | + | − |"
Three of four positive in the clinical summary table.
Head and Neck 1
Downslanted palpebral fissures FREQUENT HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Downslanted palpebral fissures | HP:0000494 | + | + | − | − |"
Two of four positive in the clinical summary table.
Immune 7
Recurrent infections VERY_FREQUENT 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:36112693 SUPPORT Human Clinical
"| Repeated infections | HP:0002719 | + | + | + | + | ✔ | ✔ |"
Positive in all four patients in the clinical summary table, which binds the same HPO term used here.
PMID:41082409 SUPPORT Human Clinical
"Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder, characterized by cytopenias, recurrent infections, and failure to thrive associated with biallelic mutation in DPP9 gene."
Independent confirmation that recurrent infection is a defining rather than an incidental feature.
Recurrent herpes simplex infection VERY_FREQUENT HP:0005353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent herpes (HP:0005353). HP:0005353 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Herpes infections | HP:0005353 | + | + (facial) | + | + | ✔ |"
Positive in all four patients, with the facial distribution noted in the Turkish proband.
PMID:36112693 SUPPORT Human Clinical
"we studied a child (F2: II.4) with signs of susceptibility to infections consisting of recurrent facial HSV lesions and airway inflammation, including chronic intermittent asthma and primary pulmonary tuberculosis"
The presenting picture in the index child, with the herpetic and the airway components together.
Selective immunodeficiency HP:0002721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Selective immunodeficiency, annotated with Immunodeficiency (HP:0002721). HP:0002721 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Selective immunodeficiency | HP:0002721 | + | + | n.d. | n.d. |"
Positive in both patients assessed and not determined in the other two, which is why no frequency is asserted for this feature.
Severe allergies FREQUENT Allergy HP:0012393 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe allergies, annotated with Allergy (HP:0012393), qualified as severity severe. HP:0012393 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Severe allergies | HP:0012393 | + (sesame) | + | − | − |"
Two of four positive in the clinical summary table, with the sesame allergen recorded for one.
Atopic dermatitis FREQUENT HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile atopic dermatitis, annotated with Atopic dermatitis (HP:0001047), qualified as infantile onset. HP:0001047 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (3 references)
PMID:36112693 SUPPORT Human Clinical
"| Atopic dermatitis | HP:0001047 | + | + | − | − |"
Two of four positive in the clinical summary table.
PMID:36112693 SUPPORT Human Clinical
"The milder skin manifestations seen in DPP9 patients may be explained by the presence of active DPP8 which we have shown can compensate for DPP9 deficiency in human cells."
The authors' explanation for why the cutaneous phenotype is attenuated relative to NLRP1 gain-of-function disease.
PMID:36112693 SUPPORT Human Clinical
"| Infantile eczema | HP:0000964 | + (after BM transplantation) | + | − | − |"
The infantile-eczema row of the same table, positive in the same two patients, which is the onset information folded into this entry.
Recurrent bronchitis FREQUENT HP:0012387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchitis (HP:0012387), qualified as temporality recurrent. HP:0012387 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Bronchitis | HP:0012387 | + | + | − | + |"
Three of four positive in the clinical summary table.
Asthma FREQUENT HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Asthma | HP:0002099 | − | + | − | + |"
Two of four positive in the clinical summary table.
Integument 2
Hypopigmented and hyperpigmented macules FREQUENT Hyperpigmented/hypopigmented macules HP:0007441 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmented/hypopigmented macules (HP:0007441). HP:0007441 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Hypo- and hyper-pigmented macules | HP:0007441 | + | + | + | − |"
Three of four positive in the clinical summary table.
PMID:36112693 SUPPORT Human Clinical
"Four patients displaying skin pigment abnormalities, poor growth, immune-associated defects and pancytopenia were identified to harbor biallelic DPP9 variants."
Names pigment abnormality as one of the four cohort-defining features.
Fair hair FREQUENT HP:0002286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fair hair (HP:0002286). HP:0002286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Fair hair | HP:0002286 | + | + | − | − |"
Two of four positive in the clinical summary table.
Metabolism 1
Periodic fever VERY_FREQUENT HP:0032323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periodic fever (HP:0032323). HP:0032323 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Recurrent fevers | HP:0032323 | + | bimonthly | + | + | ✔ | ✔ |"
Positive in all four, with the episode frequency recorded for one. The table's row label reads "Recurrent fevers"; HP:0032323 is the term it binds, whose canonical label is Periodic fever.
PMID:36112693 SUPPORT Human Clinical
"Both diseases appear to manifest with recurrent episodes of fevers, auto-immune anemia and a general failure to thrive."
Restates the febrile pattern in prose, in the paper's comparison with NLRP1-associated AIADK.
Musculoskeletal 1
Hemivertebrae HP:0002937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemivertebrae (HP:0002937). HP:0002937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Hemivertebrae | HP:0002937 | n.d. | n.d. | + | + |"
Positive in both patients assessed and not determined in the other two, which is why no frequency is asserted for this feature.
Nervous System 4
Specific learning disability FREQUENT HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Learning Disability | HP:0001328 | + | + | − | + |"
Three of four positive in the clinical summary table.
Delayed speech and language development FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Speech delay | HP:0000750 | + | + | − | + |"
Three of four positive in the clinical summary table.
Slurred speech FREQUENT HP:0001350 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Slurred speech (HP:0001350). HP:0001350 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Slurred speech | HP:0001350 | + | + | − | − |"
Two of four positive in the clinical summary table.
Autism spectrum disorder FREQUENT Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| Autism spectrum disorder | HP:0000729 | + | − | − | + |"
Two of four positive in the clinical summary table. HP:0000729 carries "Autism spectrum disorder" as an exact synonym of its canonical label Autistic behavior, which is why the row label and the bound term differ.
Growth 3
Failure to thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"These included failure to thrive (consisting of poor weight gain, growing below the 3rd percentile), skin manifestations, pancytopenia and susceptibility to infections, which in the case of F1: II.2, F3: II:11 and III:1 required hematopoietic stem cell transplant."
Defines what failure to thrive meant in this cohort and names it as one of the shared features.
Proportionate short stature VERY_FREQUENT HP:0003508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proportionate short stature (HP:0003508). HP:0003508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"| Proportionate short stature | HP:0003508 | + | + | + (−2.1 SD) | + (−1.8 SD) | ✔ | ✔ |"
Positive in all four with the standard-deviation scores for the two patients in whom they were recorded.
PMID:36112693 SUPPORT Model Organism
"Overall, these results suggest inflammasome-independent roles of DPP9 relating to stature and lung inflammation, which is consistent with the broad range of processes regulated by DPP9."
The animal evidence that the growth phenotype is not simply downstream of the inflammasome. Cited for the mechanistic reading in the description, not for the human frequency.
Intrauterine growth restriction FREQUENT Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511), qualified as antenatal onset. HP:0001511 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
PMID:36112693 SUPPORT Human Clinical
"| IUGR, (birth weight in kg) | HP:0001511 | + (2.3) | − (3.6) | − (3.2) | + (2.1) |"
Two of four scored positive, with all four birth weights given.
🧬

Genetic Associations

1
DPP9
Gene: DPP9 hgnc:18648 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DPP9 (hgnc:18648). hgnc:18648 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:36112693 SUPPORT Human Clinical
"Here, we identified three unrelated families with Hatipoğlu syndrome, an autosomal recessive DPP9 deficiency, which is characterized by immune-associated defects and dermatological anomalies."
Names the gene, the inheritance and the disease together.
PMID:36112693 SUPPORT Human Clinical
"No homozygous damaging variants have been reported for DPP9 which is significantly averse to loss-of-function mutations according to genomAD (12)."
Population constraint on the gene, quoted as the source prints it, including its spelling of gnomAD.
PMID:36112693 SUPPORT Human Clinical
"The missense mutation p.G167S found in proband F1: II.2 affected a residue in a flexible loop that was located at the periphery of the DPP9 substrate binding site (Fig. 1D)."
The structural placement of the one missense allele in the series, which is the basis for calling it hypomorphic rather than null.
Variants (4)
c.331C>T (p.R111*)
Homozygous in both affected cousins of the consanguineous Bedouin family.
c.641C>G (p.S214*)
Maternally inherited nonsense allele in the compound heterozygous proband.
c.449G>A (p.G167S)
Paternally inherited missense allele in the same proband, affecting a residue in a flexible loop at the periphery of the DPP9 substrate binding site and predicted to diminish substrate binding or catalytic efficiency.
c.2551C>T (p.Q851*)
Homozygous in the Turkish proband; no endogenous DPP9 protein was detectable in that patient's cells.
💊

Medical Actions

3
Allogeneic haematopoietic stem cell transplantation
Action: allogeneic haematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic haematopoietic stem cell transplantation, annotated with Allogeneic Hematopoietic Stem Cell Transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089
Platform: Cell therapy
The only intervention reported to address the marrow failure. Three of the four children in the founding cohort required it, and the 2026 mechanistic study describes transplantation as what current treatment requires. Post-transplant outcome data are not available in the published cohort, and whether transplantation changes the cutaneous or neurodevelopmental features is unknown - it replaces the haematopoietic compartment, which is the compartment the CARD8 mechanism destroys, and says nothing about DPP9 function elsewhere.
Mechanism Target:
Bone Marrow Stem and Progenitor Depletion — Transplantation replaces the depleted DPP9-deficient stem cell pool with donor cells that retain DPP9 and so are not subject to CARD8-driven pyroptosis.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"These included failure to thrive (consisting of poor weight gain, growing below the 3rd percentile), skin manifestations, pancytopenia and susceptibility to infections, which in the case of F1: II.2, F3: II:11 and III:1 required hematopoietic stem cell transplant."
Names the three of four patients who required transplantation and the features that drove it.
PMID:42741941 SUPPORT BACKGROUND Human Clinical
"Current treatment requires bone marrow transplantations (1)."
A second group's statement of the current standard. It is an introductory sentence citing the founding cohort rather than a result of this paper, which is why it is graded HUMAN_CLINICAL for the evidence it describes and BACKGROUND for where it sits in this publication.
Red cell transfusion support
Action: blood transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is blood transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Platform: Other
Supportive rather than disease-modifying. The twins needed repeated transfusions and repeated hospitalisation for the anaemia before the diagnosis was made, which is the practical shape of the disease for a family in the months before exome results return.
Show evidence (1 reference)
PMID:41082409 SUPPORT Human Clinical
"We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12..."
The reported transfusion requirement. This is a two-patient observation, not a management guideline.
IL-1 pathway blockade (proposed)
Action: interleukin-1 receptor antagonist therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is interleukin-1 receptor antagonist therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: anakinra NCIT:C38717 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (NCIT:C38717). NCIT:C38717 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Proposed, not established. The animal genetics are the argument: removing a single copy of Il-1r was enough to produce an almost normal adult mutant mouse, and the authors raise IL-1 receptor antagonism as a way to get part of that effect pharmacologically. No patient outcome on anakinra is reported in the sources cited in this entry. The 2026 humanized-mouse work also bounds what this could be expected to do: the haematopoietic arm runs through CARD8 and caspase-1 and was not rescued by removing NLRP1, so IL-1 blockade is a rationale for the inflammatory arm rather than for the marrow failure.
Mechanism Target:
INHIBITS IL-1-Driven Cutaneous and Systemic Inflammation — Blocking the IL-1 receptor targets the effector node the animal rescues act on.
Show evidence (2 references)
PMID:36112693 SUPPORT Model Organism
"it raises the possibility that even partial inhibition of the NLRP1-inflammasome pathway, with IL-1Ra (anakinra) for example, would provide some therapeutic benefit for DPP9 deficient patients"
The authors' proposal, quoted with its hedge intact. It is a mechanism-based rationale drawn from mouse genetics, not a reported patient response.
PMID:42741941 REFUTE Model Organism
"Deletion of CARD8 or CASP1 rescued cytopenia and loss of DPP9-deficient bone marrow stem cells, whereas NLRP1 deficiency did not."
Cuts against the NLRP1/IL-1 rationale for the haematological phenotype specifically: the arm that produces the cytopenia was not rescued by removing NLRP1. It does not bear on the cutaneous arm.
🔬

Diagnosis

2
Exome sequencing identifying biallelic DPP9 variants
The diagnosis has been made by exome sequencing in every published case. There is no recurrent allele and the reported variants are private to each family, so a targeted single-variant test has nothing to target; what matters clinically is that DPP9 is included on the bone-marrow-failure and inborn-error-of-immunity panels being run.
Show evidence (1 reference)
PMID:41082409 SUPPORT Human Clinical
"whole exome sequencing displayed DPP9 mutation in both the twins"
Exome sequencing making the diagnosis in the most recently reported patients.
Dihydrorhodamine testing is not specific in this disease
In the twin case the dihydrorhodamine test was positive and initially suggested chronic granulomatous disease, until exome sequencing redirected the diagnosis. This is one report rather than a characterised feature of the disease, but it is the kind of finding that can stop a workup at the wrong answer, so it is recorded as a differential-diagnosis caveat and not as a diagnostic criterion.
Show evidence (1 reference)
PMID:41082409 SUPPORT Human Clinical
"Immunodeficiency workup showed positive Dihydrorhodamine test suggestive of chronic granulomatous disease and whole exome sequencing displayed DPP9 mutation in both the twins."
The misleading result and the test that resolved it, in one sentence.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Six published patients as of this curation: four children from three unrelated families in the 2022 founding report, and twin siblings in a 2025 case report. No prevalence or incidence estimate exists, and none should be inferred from a cohort this size.
Show evidence (2 references)
PMID:36112693 SUPPORT Human Clinical
"The study included 4 affected children from 3 distinct families."
The exact patient count of the founding cohort.
PMID:41082409 SUPPORT Human Clinical
"We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12..."
The two additional published patients, with their age at presentation.
🧫

Experimental Models

1
MISTRG6 humanized mice engrafted with CRISPR-edited human CD34+ HSPCs OTHER
Not an animal model of the disease but a human-cell system read out in a mouse host: human CD34+ haematopoietic stem and progenitor cells are CRISPR-edited to delete DPP9 and engrafted into MISTRG6 mice. Because the cells under study are human, the CARD8 sensor that mice lack is present, and the arm no conventional mouse model can show becomes visible. Deleting CARD8 or CASP1 rescued the cells; deleting NLRP1 did not.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:42741941
Pathograph links
Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells recapitulates fidelity: high observes: cellular The system in which this node was demonstrated, in the human cell type the node names.
Limitations: An engineered deletion in edited cells rather than a patient genotype, and an engraftment setting in which transplantation stress may itself be the trigger the authors could not identify. The skin and neurodevelopmental arms of the disease are outside what an HSPC system can address.
Readouts
Lactate dehydrogenase release from cultured HSPCs
Direction: ABOLISHED
Interpretation: Pyroptotic membrane rupture, abolished when CARD8 or CASP1 is deleted.
Show evidence (1 reference)
PMID:42741941 SUPPORT In Vitro
"Pyroptosis was completely abrogated in HSPCs that lacked CARD8 or CASP1, suggesting that HSPCs undergo CARD8-dependent pyroptosis (Figure 5A)."
The measurement and its direction under the rescue genotypes.
Show evidence (1 reference)
PMID:42741941 SUPPORT Model Organism
"Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic."
Establishes that the system reproduces the human phenotype it is being used to explain.
🐁

Animal Models

2
Dpp9 S759A catalytically inactive knock-in mouse
The model that established the inflammasome dependence of DPP9 deficiency in vivo. Homozygotes die within a day of birth, and that lethality is rescued by removing a single copy of Nlrp1a/b/c, Asc, Gsdmd or Il-1r - but not Il-18. It does not model the human blood phenotype: mutant mice have no significant haematological abnormality.
Species
Mouse
Genotype
Dpp9 S759A homozygous knock-in (catalytically inactive DPP9)
Publication
PMID:36112693
Pathograph links
IL-1-Driven Cutaneous and Systemic Inflammation recapitulates fidelity: moderate observes: organism The genetic rescue series is the strongest available evidence that IL-1 receptor signalling downstream of the NLRP1 inflammasome is the limiting effector of DPP9 deficiency in a whole animal.
Limitations: Mouse Nlrp1 paralogues are not the human sensor, and the readout rescued is neonatal lethality rather than any feature of the human disease.
Show evidence (1 reference)
PMID:36112693 SUPPORT Model Organism
"The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice."
The rescue series that grounds this link, including the negative result for Il-18.
Bone Marrow Stem and Progenitor Depletion fails to recapitulate fidelity: low observes: organism The mouse does not develop the cytopenia that defines the human disease.
Limitations: Mice have no CARD8 gene at all, so the sensor that drives human HSPC pyroptosis is absent from the model by construction. No refinement of a conventional mouse model can recover this arm.
Show evidence (2 references)
PMID:36112693 SUPPORT Model Organism
"Thus, we do not observe significant haematological abnormalities similar to those observed in patients with germline loss of DPP9 activity."
The explicit negative result, which is what this link asserts: the model does not reproduce the patients' haematological phenotype. The quote is a negative finding about the mouse and a positive one about the failure-to-recapitulate claim it is attached to.
+ 1 more reference
Show evidence (1 reference)
PMID:36112693 SUPPORT Model Organism
"Dpp9S759A/S759A mice died within one day of birth through an unknown mechanism."
The baseline phenotype of the model, against which every rescue in the series is measured.
dpp9 knockout zebrafish
An independent model organism giving the same answer on the inflammasome adaptor: inactivating asc partially rescues the lethality of dpp9 deficiency.
Species
Zebrafish
Genotype
dpp9 knockout
Publication
PMID:36112693
Pathograph links
IL-1-Driven Cutaneous and Systemic Inflammation partially recapitulates fidelity: low observes: organism Corroborates ASC dependence in a second species, which is why the inflammasome reading of DPP9 deficiency does not rest on mouse genetics alone.
Limitations: The rescue is partial, the readout is survival rather than inflammation, and zebrafish inflammasome sensors are more distant from human NLRP1 than the mouse paralogues are.
Show evidence (1 reference)
PMID:36112693 SUPPORT Model Organism
"Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish."
The rescue, with the partial qualifier the source states.
{ }

Source YAML

click to show 
name: Hatipoglu Immunodeficiency Syndrome
creation_date: "2026-09-23T19:41:29Z"
category: Mendelian
synonyms:
- HATIS
- Hatipoglu syndrome
- DPP9 deficiency
description: >-
  Hatipoglu immunodeficiency syndrome is an autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function or hypomorphic variants in DPP9
  (OMIM 620331). DPP9 is a cytosolic dipeptidyl peptidase whose job in innate
  immunity is restraint: it holds the two FIIND-domain inflammasome sensors, NLRP1
  and CARD8, in a repressed ternary complex. When DPP9 is lost, that restraint is
  lifted and the sensors fire without any danger signal, so the disease is a
  derepression disorder rather than a sensor gain-of-function one.

  The clinical picture in the four children of the founding cohort was a triad of
  failure to thrive, skin manifestations and pancytopenia, together with
  susceptibility to bacterial and herpesviral infection. Three of the four needed
  haematopoietic stem cell transplantation for the marrow phenotype. Presentation
  is paediatric throughout - growth restriction from infancy, recurrent fever and
  transfusion-dependent anaemia - and the reported cohort is still small enough
  that patient counts, not frequencies, are the honest unit.

  Two things make the mechanism worth reading carefully. First, it splits by tissue
  and by species: NLRP1 drives the skin arm, demonstrated in patient keratinocytes,
  while the haematopoietic arm runs through CARD8, a gene that does not exist in
  the mouse - which is why Dpp9-mutant mice have normal haematopoiesis while the
  human disease is defined by marrow failure. Second, that split has a therapeutic
  consequence: IL-1 blockade addresses the NLRP1/IL-1 arm the animal models rescue,
  but the CARD8-driven pyroptosis of human stem cells was rescued by deleting CARD8
  or CASP1 and not by deleting NLRP1.
disease_term:
  preferred_term: hatipoglu immunodeficiency syndrome
  term:
    id: MONDO:0957229
    label: hatipoglu immunodeficiency syndrome
parents:
- inborn error of immunity
- inflammasomopathy
- bone marrow failure syndrome
references:
- reference: PMID:36112693
  title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
- reference: PMID:42741941
  title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
- reference: PMID:41082409
  title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
inheritance:
- name: Autosomal recessive
  description: >-
    Every reported affected individual carries two damaged DPP9 alleles - homozygous
    stop-gained variants in the two consanguineous families, and a compound
    heterozygous missense/nonsense pair in the third. Parents and unaffected siblings
    were heterozygous or non-carriers. The twins of the 2025 case report were born to
    a non-consanguineous couple, so consanguinity enriches for the disease without
    being required for it.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each propositus was shown to segregate a homozygous germline stop-gained variant (c.331C>T; p.R111*) while available parents and siblings were either heterozygous or non-carrier consistent with Mendelian recessive inheritance."
    explanation: >-
      Segregation in the Bedouin family, stated as establishing recessive inheritance.
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder, characterized by cytopenias, recurrent infections, and failure to thrive associated with biallelic mutation in DPP9 gene."
    explanation: >-
      An independent group naming the inheritance mode and the biallelic requirement.
pathophysiology:
- name: Biallelic DPP9 Loss-of-Function Variants
  description: >-
    The initiating lesion. Germline nonsense variants (p.R111*, p.S214*, p.Q851*)
    and one missense variant (p.G167S) affecting the substrate-binding site behave
    as knockout or hypomorphic alleles. The catalytic domain sits at the C-terminus,
    so the stop-gained alleles are expected to abolish enzymatic activity outright;
    no DPP9 protein at all was detectable in the fibroblasts of the p.Q851*
    homozygote.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
  genes:
  - preferred_term: DPP9
    term:
      id: hgnc:18648
      label: DPP9
  molecular_functions:
  - preferred_term: DPP9 dipeptidyl peptidase activity
    modifier: DECREASED
    term:
      id: GO:0008239
      label: dipeptidyl-peptidase activity
  downstream:
  - target: Proportionate short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn from the lesion rather than from the inflammasome node on purpose. In the
      mouse, runting persisted after NLRP1 deletion, so the growth phenotype is
      attributed to a DPP9 function that does not run through the inflammasome. Which
      function is not known, which is what the unknown-intermediates link type records.
    evidence:
    - reference: PMID:36112693
      reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, these results suggest inflammasome-independent roles of DPP9 relating to stature and lung inflammation, which is consistent with the broad range of processes regulated by DPP9."
      explanation: >-
        Assigns stature to an inflammasome-independent DPP9 role, which is what routes
        this edge from the lesion node rather than from the IL-1 effector node.
  - target: Loss of DPP9 Restraint on FIIND Inflammasome Sensors
    causal_link_type: DIRECT
    description: >-
      The patient alleles are less able to hold NLRP1 in its inactive state, which is
      the function the downstream node loses.
    evidence:
    - reference: PMID:36112693
      reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Taken together, these experiments suggest that these DPP9 patient variants are less able to maintain NLRP1 in the inactive state."
      explanation: >-
        Connects the specific patient alleles to the loss of repression, rather than
        citing loss of DPP9 function and NLRP1 derepression as two separate facts.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1"
    explanation: >-
      Classifies the allele series as hypomorphic or null, which is what the
      LOSS_OF_FUNCTION category on this node asserts.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The stop-gain mutations found in these 3 probands from Families 2 and 3 were expected to completely abolish the enzymatic activity of DPP9, since its catalytic domain is situated at the C-terminus."
    explanation: >-
      The structural reason the nonsense alleles are nulls rather than partial-activity
      alleles.
- name: Loss of DPP9 Restraint on FIIND Inflammasome Sensors
  description: >-
    DPP9 normally sits in a ternary complex with full-length NLRP1 and the
    autoproteolytically released NLRP1 C-terminal UPA-CARD fragment, sequestering
    that fragment so it cannot oligomerise. CARD8 is held by an analogous, though
    not identical, DPP9 complex - the CARD8 C-terminus does not engage the DPP9
    active site the way NLRP1's does, and DPP9's catalytic activity rather than its
    binding is what restrains CARD8. Losing DPP9 removes both restraints at once,
    which is why one enzyme deficiency produces two tissue-specific arms of disease.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: DPP9 restraint of FIIND sensor inflammasome signalling
    modifier: DECREASED
    term:
      id: GO:0141086
      label: negative regulation of inflammasome-mediated signaling pathway
  downstream:
  - target: NLRP1 Inflammasome Activation in Keratinocytes
    causal_link_type: DIRECT
  - target: CARD8 Inflammasome Activation in Hematopoietic Progenitors
    causal_link_type: DIRECT
    description: >-
      The human haematopoietic arm. Deleting DPP9 in human CD34+ cells activates
      CARD8, and it is this branch rather than the NLRP1 branch that kills the cells.
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mechanistically, DPP9 deficiency led to activation of the CARD8 inflammasome, resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death."
      explanation: >-
        States the edge and, in the same sentence, that the NLRP1 branch does not
        account for it.
  evidence:
  - reference: PMID:33731932
    reference_title: "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT."
    explanation: >-
      The structural basis of the repression this node loses. Note the source's own
      typography: it prints "NLRPT CT" where it means the NLRP1 C-terminal fragment,
      and the quote is reproduced as printed.
  - reference: PMID:34019797
    reference_title: "Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we report cryoelectron microscopy (cryo-EM) structures of CARD8 bound to DPP9, revealing a repressive ternary complex consisting of DPP9, full-length CARD8, and CARD8-CT."
    explanation: >-
      The same repressive architecture for CARD8, which is the sensor behind the
      haematopoietic arm of this disease.
  - reference: PMID:31525884
    reference_title: "DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, wild-type, but not catalytically inactive mutant, DPP9 rescues CARD8-mediated cell death in DPP9 knockout cells."
    explanation: >-
      Establishes that it is DPP9 catalytic activity that restrains CARD8, which is why
      hypomorphic missense alleles and nulls converge on the same downstream node.
- name: NLRP1 Inflammasome Activation in Keratinocytes
  description: >-
    In skin, the liberated NLRP1 C-terminal fragment oligomerises, recruits ASC and
    pro-caspase-1, and fires without any exogenous trigger. Patient keratinocytes do
    this spontaneously in culture. The release is real but modest compared with
    pharmacological DPP8/DPP9 inhibition of control cells, because DPP8 remains
    intact in these patients and partially covers for the missing DPP9.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: interleukin-1 beta production
    modifier: INCREASED
    term:
      id: GO:0032611
      label: interleukin-1 beta production
  downstream:
  - target: IL-1-Driven Cutaneous and Systemic Inflammation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrated that the proband keratinocytes, as do keratinocytes from patients with gain-of-function NLRP1 mutations (5), spontaneously secreted active IL-1β and IL-18 into the media without any exogenous stimulus."
    explanation: >-
      Direct human-cell demonstration of unprovoked inflammasome output, which is what
      this node claims.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data indicate that loss of DPP9 function in patient-derived cells could indeed be partially compensated by DPP8, accounting for their modest yet significant IL-1β release and cell death."
    explanation: >-
      The DPP8 compensation that sets the magnitude of this node, and the reason the
      skin phenotype is milder than in NLRP1 gain-of-function disease.
- name: CARD8 Inflammasome Activation in Hematopoietic Progenitors
  description: >-
    The arm that defines the disease clinically, and the one no conventional mouse
    model could show. Human CD34+ haematopoietic stem and progenitor cells express
    CARD8 along with the full downstream apparatus. With DPP9 gone, CARD8 assembles
    and activates caspase-1. What triggers CARD8 in these cells is not established -
    the authors propose an as-yet-undefined cellular stress signal - so this node
    records de-repression, not a named trigger.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: CARD8 inflammasome assembly
    modifier: INCREASED
    term:
      id: GO:0140633
      label: CARD8 inflammasome complex assembly
  downstream:
  - target: Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells
    causal_link_type: DIRECT
    description: >-
      Deleting CASP1 rescues the cells, which is what makes the death caspase-1
      dependent rather than merely caspase-1 associated.
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Pyroptosis was completely abrogated in HSPCs that lacked CARD8 or CASP1, suggesting that HSPCs undergo CARD8-dependent pyroptosis (Figure 5A)."
      explanation: >-
        The genetic epistasis behind this edge, in both the sensor and the protease.
  evidence:
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Downstream effectors including CASP1 and GSDMD were similarly expressed, indicating that human HSPCs possess the complete molecular apparatus required for inflammasome-driven pyroptosis (Figure 4D)."
    explanation: >-
      Establishes that the machinery this node needs is present in the cell type the
      node names.
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CARD8 may be triggered by a yet-to-be-defined cellular stress signal during transplantation of HSPCs and induce their pyroptosis in the absence of DPP9."
    explanation: >-
      Records that the proximal trigger is unknown, which is why this node is written
      as de-repression rather than as a response to a named danger signal.
- name: Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells
  description: >-
    Active caspase-1 drives gasdermin-mediated membrane rupture and kills the cell.
    In the humanized-mouse system the loss is cell intrinsic: DPP9-deleted human
    HSPCs die whether or not unedited cells are present alongside them.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: pyroptotic inflammatory response
    modifier: INCREASED
    term:
      id: GO:0070269
      label: pyroptotic inflammatory response
  downstream:
  - target: Bone Marrow Stem and Progenitor Depletion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "HSPC numbers were rescued by deletion of CARD8, suggesting that CARD8 mediated pyroptosis of DPP9–/– HSPCs in vivo, including HSCs and MPPs (Figure 5, B and C)."
      explanation: >-
        Rescuing the pyroptosis restores the progenitor pool, which is the edge from
        cell death to compartment depletion.
  evidence:
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The recapitulation of patient disease and the cell-intrinsic loss of stem cells suggest that the susceptibility to pyroptosis was a property of HSPCs rather than a consequence of transplantation models."
    explanation: >-
      Supports the death being a property of the DPP9-deficient cell itself rather than
      of its environment.
- name: Bone Marrow Stem and Progenitor Depletion
  description: >-
    Loss of the stem and progenitor pool is what turns a molecular derepression into
    the marrow failure that drives the clinical course. It is the point at which the
    disease becomes transplant-dependent.
  biological_scale: TISSUE
  downstream:
  - target: Pancytopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Taken together, these results reveal that DPP9–/– HSPCs undergo CARD8-mediated pyroptosis after transplantation and that loss of bone marrow stem cells leads to peripheral cytopenia."
      explanation: >-
        States the marrow-to-peripheral-blood step directly.
  - target: Anemia
    causal_link_type: DIRECT
  - target: Petechiae
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The thrombocytopenic limb of the pancytopenia, read through to the skin. The
      intermediate is megakaryocyte and platelet loss, which the cited sources report
      only as part of the pancytopenia rather than measuring separately, so the edge
      is an inference from the cytopenia and not a demonstrated platelet result.
  - target: Recurrent infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The infectious susceptibility is read here as downstream of marrow failure, which
      is how the 2026 study frames it, rather than as an independent lesion of immune
      function.
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "How human DPP9 mutations cause pancytopenia remains an important question, since pancytopenia probably causes recurrent infection due to the lack of immune cells and the need for bone marrow transplantation."
      explanation: >-
        The authors' own reading of the causal order. Their hedge ("probably") is worth
        keeping in view: this edge is an inference from the cytopenia, not a separately
        demonstrated result.
  evidence:
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic."
    explanation: >-
      Both compartments lose cells, which is what this node asserts.
- name: IL-1-Driven Cutaneous and Systemic Inflammation
  description: >-
    Mature IL-1 beta released from unprovoked inflammasome activation is the
    effector of the non-haematological arm. The animal genetics point at IL-1 rather
    than IL-18: removing one copy of Il-1r rescued the mutant mouse, while removing
    Il-18 did not.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: interleukin-1 beta production
    modifier: INCREASED
    term:
      id: GO:0032611
      label: interleukin-1 beta production
  downstream:
  - target: Periodic fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Atopic dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice."
    explanation: >-
      Identifies IL-1 receptor signalling, and not IL-18, as the limiting effector in
      the model - the reason this node is written around IL-1.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling."
    explanation: >-
      The summary claim for this node in the two animal models. It is a model-organism
      claim: the human haematopoietic arm turned out not to follow it.
phenotypes:
- category: Hematological
  name: Pancytopenia
  description: >-
    Present in all four children of the founding cohort and the feature that drove
    three of them to transplantation. It is the treatment-defining problem of the
    disease.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Pancytopenia | HP:0001876 | + | + | + | + | ✔ |"
    explanation: >-
      The clinical summary table, scored positive in each of the four patients and
      marked as present in all cases.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants."
    explanation: >-
      The cohort-level statement, naming pancytopenia as one of the defining features.
- category: Hematological
  name: Anemia
  description: >-
    Universal in the founding cohort, and the presenting problem in the 2025 twins,
    where it was macrocytic, transfusion-dependent and unresponsive to vitamin B12 -
    a pattern worth knowing because it invites a nutritional workup that will not
    explain it.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Anemia | HP:0001903 | + | + | + | + | ✔ |"
    explanation: >-
      Positive in all four patients in the clinical summary table.
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12 supplementation."
    explanation: >-
      The independent case report, giving the age at presentation, the severity and the
      macrocytic, B12-unresponsive character of the anaemia.
- category: Hematological
  name: Petechiae
  description: >-
    Scored in all four patients. It sits at the interface of the haematological and
    the cutaneous phenotype and is the visible face of the thrombocytopenic component
    of the pancytopenia.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Petechiae | HP:0000967 | + | + | + | + | ✔ |"
    explanation: >-
      Positive in all four patients in the clinical summary table.
- category: Immunological
  name: Recurrent infections
  description: >-
    Bacterial and viral, and present in every reported patient. Sites reported across
    the cohort and the twin case include sinopulmonary infection, bronchitis, otitis
    media and, in one child, primary pulmonary tuberculosis.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Repeated infections | HP:0002719 | + | + | + | + | ✔ | ✔ |"
    explanation: >-
      Positive in all four patients in the clinical summary table, which binds the same
      HPO term used here.
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder, characterized by cytopenias, recurrent infections, and failure to thrive associated with biallelic mutation in DPP9 gene."
    explanation: >-
      Independent confirmation that recurrent infection is a defining rather than an
      incidental feature.
- category: Immunological
  name: Recurrent herpes simplex infection
  description: >-
    Scored in all four patients, and facial herpes simplex lesions were part of what
    brought the Turkish proband to attention as a possible inborn error of immunity.
  phenotype_term:
    preferred_term: Recurrent herpes
    term:
      id: HP:0005353
      label: Recurrent herpes
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Herpes infections | HP:0005353 | + | + (facial) | + | + | ✔ |"
    explanation: >-
      Positive in all four patients, with the facial distribution noted in the Turkish
      proband.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we studied a child (F2: II.4) with signs of susceptibility to infections consisting of recurrent facial HSV lesions and airway inflammation, including chronic intermittent asthma and primary pulmonary tuberculosis"
    explanation: >-
      The presenting picture in the index child, with the herpetic and the airway
      components together.
- category: Immunological
  name: Periodic fever
  description: >-
    Recurrent febrile episodes in every patient, bimonthly in one. These are the
    autoinflammatory face of the disease and sit alongside, rather than instead of,
    the infections.
  phenotype_term:
    preferred_term: Periodic fever
    term:
      id: HP:0032323
      label: Periodic fever
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Recurrent fevers | HP:0032323 | + | bimonthly | + | + | ✔ | ✔ |"
    explanation: >-
      Positive in all four, with the episode frequency recorded for one. The table's row
      label reads "Recurrent fevers"; HP:0032323 is the term it binds, whose canonical
      label is Periodic fever.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both diseases appear to manifest with recurrent episodes of fevers, auto-immune anemia and a general failure to thrive."
    explanation: >-
      Restates the febrile pattern in prose, in the paper's comparison with
      NLRP1-associated AIADK.
- category: Immunological
  name: Selective immunodeficiency
  description: >-
    Scored positive in both children in whom it was assessed and not determined in the
    other two, so the denominator here is two rather than four. The founding paper
    binds the general HPO immunodeficiency term to this row and does not say which
    compartment was selectively deficient, so nothing narrower than that term is
    assertable from the source - HPO has no "selective immunodeficiency" term, and the
    immunological workup behind the row is not reported.
  phenotype_term:
    preferred_term: Selective immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Selective immunodeficiency | HP:0002721 | + | + | n.d. | n.d. |"
    explanation: >-
      Positive in both patients assessed and not determined in the other two, which is
      why no frequency is asserted for this feature.
- category: Immunological
  name: Severe allergies
  description: >-
    Two of the four, one of them to sesame. These are the same two children who carry
    the eczema, so atopy runs alongside the infections in this disease rather than
    replacing them; the asthma, by contrast, is scored in a different pair, so the
    atopic features do not cluster in one child. Nothing in the published work links
    the allergy to the inflammasome mechanism.
  phenotype_term:
    preferred_term: Severe allergies
    term:
      id: HP:0012393
      label: Allergy
    severity: SEVERE
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Severe allergies | HP:0012393 | + (sesame) | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table, with the sesame allergen
      recorded for one.
- category: Growth
  name: Failure to thrive
  description: >-
    Poor weight gain below the third percentile in every patient. Paediatrically this
    is often the first thing measured rather than the first thing complained of, and
    in this disease it is present from infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These included failure to thrive (consisting of poor weight gain, growing below the 3rd percentile), skin manifestations, pancytopenia and susceptibility to infections, which in the case of F1: II.2, F3: II:11 and III:1 required hematopoietic stem cell transplant."
    explanation: >-
      Defines what failure to thrive meant in this cohort and names it as one of the
      shared features.
- category: Growth
  name: Proportionate short stature
  description: >-
    Recorded in all four, with heights of -2.1 and -1.8 standard deviations in the two
    Bedouin cousins. The mouse model is runted too, and that runting persisted even
    when NLRP1 was deleted - so short stature may be one of the DPP9 functions that is
    not inflammasome-mediated.
  phenotype_term:
    preferred_term: Proportionate short stature
    term:
      id: HP:0003508
      label: Proportionate short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Proportionate short stature | HP:0003508 | + | + | + (−2.1 SD) | + (−1.8 SD) | ✔ | ✔ |"
    explanation: >-
      Positive in all four with the standard-deviation scores for the two patients in
      whom they were recorded.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, these results suggest inflammasome-independent roles of DPP9 relating to stature and lung inflammation, which is consistent with the broad range of processes regulated by DPP9."
    explanation: >-
      The animal evidence that the growth phenotype is not simply downstream of the
      inflammasome. Cited for the mechanistic reading in the description, not for the
      human frequency.
- category: Growth
  name: Intrauterine growth restriction
  description: >-
    Two of the four were growth restricted at birth, with birth weights of 2.1 and
    2.3 kg. This is the earliest point at which the disease is measurable and puts
    onset in the prenatal period in at least some patients.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
    onset:
      onset_category: ANTENATAL
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| IUGR, (birth weight in kg) | HP:0001511 | + (2.3) | − (3.6) | − (3.2) | + (2.1) |"
    explanation: >-
      Two of four scored positive, with all four birth weights given.
- category: Growth
  name: Poor feeding
  description: >-
    Two of the four fed poorly. It belongs next to the failure to thrive rather than
    apart from it: in an infant, poor intake is the mechanism most likely to be looked
    for first when weight gain fails, and here it is present in only half the children
    whose growth failed, so it does not account for the growth phenotype on its own.
  phenotype_term:
    preferred_term: Poor feeding
    term:
      id: HP:0011968
      label: Feeding difficulties
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Poor feeding | HP:0011968 | + | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table.
- category: Dermatological
  name: Hypopigmented and hyperpigmented macules
  description: >-
    Mixed pigmentary change is part of the cohort-defining triad. It was present in
    three of the four children and is the kind of finding that is easy to pass over
    unless the diagnosis is already in mind.
  phenotype_term:
    preferred_term: Hyperpigmented/hypopigmented macules
    term:
      id: HP:0007441
      label: Hyperpigmented/hypopigmented macules
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hypo- and hyper-pigmented macules | HP:0007441 | + | + | + | − |"
    explanation: >-
      Three of four positive in the clinical summary table.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four patients displaying skin pigment abnormalities, poor growth, immune-associated defects and pancytopenia were identified to harbor biallelic DPP9 variants."
    explanation: >-
      Names pigment abnormality as one of the four cohort-defining features.
- category: Dermatological
  name: Atopic dermatitis
  description: >-
    Eczema in two of the four, from infancy. The founding table scores these two
    children twice, once as infantile eczema and once as atopic dermatitis; both rows
    name the same two patients, and HP:0000964 Eczematoid dermatitis is the parent of
    HP:0001047 Atopic dermatitis, so the finding is curated once at the more specific
    term with the infantile onset carried here rather than split across two phenotype
    entries. In one of the two the eczema is recorded after bone marrow
    transplantation. The paper's own reading is that the skin manifestations here are
    milder than in NLRP1 gain-of-function disease because intact DPP8 partially covers
    for the missing DPP9.
  phenotype_term:
    preferred_term: Infantile atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
    onset:
      onset_category: INFANTILE
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Atopic dermatitis | HP:0001047 | + | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The milder skin manifestations seen in DPP9 patients may be explained by the presence of active DPP8 which we have shown can compensate for DPP9 deficiency in human cells."
    explanation: >-
      The authors' explanation for why the cutaneous phenotype is attenuated relative to
      NLRP1 gain-of-function disease.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Infantile eczema | HP:0000964 | + (after BM transplantation) | + | − | − |"
    explanation: >-
      The infantile-eczema row of the same table, positive in the same two patients,
      which is the onset information folded into this entry.
- category: Dermatological
  name: Fair hair
  description: >-
    Two of the four had fair hair. Read it alongside the hypo- and hyperpigmented
    macules and the premature graying reported in one child: the pigmentary phenotype
    of this disease is not confined to the skin, although nothing in the published work
    connects it to a melanocyte mechanism.
  phenotype_term:
    preferred_term: Fair hair
    term:
      id: HP:0002286
      label: Fair hair
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Fair hair | HP:0002286 | + | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table.
- category: Respiratory
  name: Recurrent bronchitis
  description: >-
    Three of the four had recurrent bronchitis. Together with the otitis media and the
    sinopulmonary infections of the twin case, the respiratory tract is the commonest
    site of infection in this disease.
  phenotype_term:
    preferred_term: Bronchitis
    term:
      id: HP:0012387
      label: Bronchitis
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Bronchitis | HP:0012387 | + | + | − | + |"
    explanation: >-
      Three of four positive in the clinical summary table.
- category: Respiratory
  name: Asthma
  description: >-
    Two of the four. In the index child the airway disease was described as chronic
    intermittent asthma alongside primary pulmonary tuberculosis, so the airway
    phenotype and the infectious susceptibility are entangled rather than separable.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Asthma | HP:0002099 | − | + | − | + |"
    explanation: >-
      Two of four positive in the clinical summary table.
- category: ENT
  name: Recurrent otitis media
  description: >-
    Three of the four were described as prone to acute otitis media - a common
    paediatric complaint whose recurrence here belongs to the immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Prone to acute otitis media | HP:0000403 | + | + | + | − |"
    explanation: >-
      Three of four positive in the clinical summary table.
- category: Neurodevelopmental
  name: Specific learning disability
  description: >-
    Reported in three of the four children. Whether it belongs to the mechanism is
    genuinely unsettled - no inflammasome-dependent route to it has been shown, and
    neither animal model addresses it. It is recorded here as an observed feature of
    the cohort, with the open question carried in the discussions section.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Learning Disability | HP:0001328 | + | + | − | + |"
    explanation: >-
      Three of four positive in the clinical summary table.
- category: Neurodevelopmental
  name: Delayed speech and language development
  description: >-
    Three of the four had speech delay, two of them with slurred speech as well. As
    with the learning disability, the mechanistic link is not established.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Speech delay | HP:0000750 | + | + | − | + |"
    explanation: >-
      Three of four positive in the clinical summary table.
- category: Neurodevelopmental
  name: Slurred speech
  description: >-
    Two of the four, both of them among the three with speech delay. Slurred speech is
    a motor-output finding rather than a language one, so it is curated separately from
    the delay rather than as a description of it; whether the two share a mechanism here
    is unknown, as is whether either is inflammasome-mediated.
  phenotype_term:
    preferred_term: Slurred speech
    term:
      id: HP:0001350
      label: Slurred speech
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Slurred speech | HP:0001350 | + | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table.
- category: Neurodevelopmental
  name: Autism spectrum disorder
  description: >-
    Two of the four. Notably these are not the same two children as the slurred speech
    row - the autism is scored in the Ashkenazi proband and one Bedouin cousin - so the
    neurodevelopmental findings in this cohort do not travel together as a single
    syndrome-specific profile. As with the learning disability and the speech delay, no
    inflammasome-dependent route to it has been shown.
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Autism spectrum disorder | HP:0000729 | + | − | − | + |"
    explanation: >-
      Two of four positive in the clinical summary table. HP:0000729 carries "Autism
      spectrum disorder" as an exact synonym of its canonical label Autistic behavior,
      which is why the row label and the bound term differ.
- category: Craniofacial
  name: Downslanted palpebral fissures
  description: >-
    Two of the four. This is the only craniofacial finding in the cohort scored in more
    than one child - the broad forehead was seen in one - and with four patients it is
    not enough to describe a recognisable facial gestalt for this disease.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Downslanted palpebral fissures | HP:0000494 | + | + | − | − |"
    explanation: >-
      Two of four positive in the clinical summary table.
- category: Gastrointestinal
  name: Inguinal hernia
  description: >-
    Two of the four. The founding table prints HP:0000776 against this row, which is
    the HPO term for congenital diaphragmatic hernia; the term bound here is HP:0000023
    Inguinal hernia, which is what the row label names. The snippet quotes the row as
    the source printed it, identifier included.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  frequency: FREQUENT
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Inguinal hernia | HP:0000776 | + | − | − | + |"
    explanation: >-
      Two of four positive in the clinical summary table. The quoted identifier is the
      source's; the phenotype is bound to HP:0000023 for the reason given in the
      description.
- category: Skeletal
  name: Hemivertebrae
  description: >-
    Present in both Bedouin cousins, the two patients in whom it was looked for; it was
    not determined in the other two, so the denominator here is two and not four.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hemivertebrae | HP:0002937 | n.d. | n.d. | + | + |"
    explanation: >-
      Positive in both patients assessed and not determined in the other two, which is
      why no frequency is asserted for this feature.
genetic:
- name: DPP9
  gene_term:
    preferred_term: DPP9
    term:
      id: hgnc:18648
      label: DPP9
  relationship_type: CAUSATIVE
  notes: >-
    The only gene implicated in this disease. DPP9 encodes a cytosolic dipeptidyl
    peptidase; the reported disease alleles are private to each family, so there is no
    recurrent variant to test for and diagnosis has been by exome sequencing in every
    published case. DPP9 is constrained against loss of function in population data,
    which is consistent with a recessive disease in which no homozygous damaging
    variant had previously been observed. The gene reaches the pathograph through the
    genes descriptor on the Biallelic DPP9 Loss-of-Function Variants node.
  variants:
  - name: c.331C>T (p.R111*)
    description: >-
      Homozygous in both affected cousins of the consanguineous Bedouin family.
  - name: c.641C>G (p.S214*)
    description: >-
      Maternally inherited nonsense allele in the compound heterozygous proband.
  - name: c.449G>A (p.G167S)
    description: >-
      Paternally inherited missense allele in the same proband, affecting a residue in
      a flexible loop at the periphery of the DPP9 substrate binding site and predicted
      to diminish substrate binding or catalytic efficiency.
  - name: c.2551C>T (p.Q851*)
    description: >-
      Homozygous in the Turkish proband; no endogenous DPP9 protein was detectable in
      that patient's cells.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identified three unrelated families with Hatipoğlu syndrome, an autosomal recessive DPP9 deficiency, which is characterized by immune-associated defects and dermatological anomalies."
    explanation: >-
      Names the gene, the inheritance and the disease together.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No homozygous damaging variants have been reported for DPP9 which is significantly averse to loss-of-function mutations according to genomAD (12)."
    explanation: >-
      Population constraint on the gene, quoted as the source prints it, including its
      spelling of gnomAD.
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The missense mutation p.G167S found in proband F1: II.2 affected a residue in a flexible loop that was located at the periphery of the DPP9 substrate binding site (Fig. 1D)."
    explanation: >-
      The structural placement of the one missense allele in the series, which is the
      basis for calling it hypomorphic rather than null.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Six published patients as of this curation: four children from three unrelated
    families in the 2022 founding report, and twin siblings in a 2025 case report. No
    prevalence or incidence estimate exists, and none should be inferred from a cohort
    this size.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study included 4 affected children from 3 distinct families."
    explanation: >-
      The exact patient count of the founding cohort.
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12 supplementation."
    explanation: >-
      The two additional published patients, with their age at presentation.
diagnosis:
- name: Exome sequencing identifying biallelic DPP9 variants
  description: >-
    The diagnosis has been made by exome sequencing in every published case. There is
    no recurrent allele and the reported variants are private to each family, so a
    targeted single-variant test has nothing to target; what matters clinically is
    that DPP9 is included on the bone-marrow-failure and inborn-error-of-immunity
    panels being run.
  evidence:
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whole exome sequencing displayed DPP9 mutation in both the twins"
    explanation: >-
      Exome sequencing making the diagnosis in the most recently reported patients.
- name: Dihydrorhodamine testing is not specific in this disease
  description: >-
    In the twin case the dihydrorhodamine test was positive and initially suggested
    chronic granulomatous disease, until exome sequencing redirected the diagnosis.
    This is one report rather than a characterised feature of the disease, but it is
    the kind of finding that can stop a workup at the wrong answer, so it is recorded
    as a differential-diagnosis caveat and not as a diagnostic criterion.
  evidence:
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunodeficiency workup showed positive Dihydrorhodamine test suggestive of chronic granulomatous disease and whole exome sequencing displayed DPP9 mutation in both the twins."
    explanation: >-
      The misleading result and the test that resolved it, in one sentence.
treatments:
- name: Allogeneic haematopoietic stem cell transplantation
  description: >-
    The only intervention reported to address the marrow failure. Three of the four
    children in the founding cohort required it, and the 2026 mechanistic study
    describes transplantation as what current treatment requires. Post-transplant
    outcome data are not available in the published cohort, and whether transplantation
    changes the cutaneous or neurodevelopmental features is unknown - it replaces the
    haematopoietic compartment, which is the compartment the CARD8 mechanism destroys,
    and says nothing about DPP9 function elsewhere.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic haematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Bone Marrow Stem and Progenitor Depletion
    description: >-
      Transplantation replaces the depleted DPP9-deficient stem cell pool with donor
      cells that retain DPP9 and so are not subject to CARD8-driven pyroptosis.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These included failure to thrive (consisting of poor weight gain, growing below the 3rd percentile), skin manifestations, pancytopenia and susceptibility to infections, which in the case of F1: II.2, F3: II:11 and III:1 required hematopoietic stem cell transplant."
    explanation: >-
      Names the three of four patients who required transplantation and the features
      that drove it.
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Current treatment requires bone marrow transplantations (1)."
    explanation: >-
      A second group's statement of the current standard. It is an introductory sentence
      citing the founding cohort rather than a result of this paper, which is why it is
      graded HUMAN_CLINICAL for the evidence it describes and BACKGROUND for where it
      sits in this publication.
- name: Red cell transfusion support
  description: >-
    Supportive rather than disease-modifying. The twins needed repeated transfusions
    and repeated hospitalisation for the anaemia before the diagnosis was made, which
    is the practical shape of the disease for a family in the months before exome
    results return.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:41082409
    reference_title: "Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 8-month-old pair of twins born to a nonconsanguineous marriage with similar presentation showing severe anemia and recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions with investigations suggestive of macrocytic anemia unresponsive to B12 supplementation."
    explanation: >-
      The reported transfusion requirement. This is a two-patient observation, not a
      management guideline.
- name: IL-1 pathway blockade (proposed)
  description: >-
    Proposed, not established. The animal genetics are the argument: removing a single
    copy of Il-1r was enough to produce an almost normal adult mutant mouse, and the
    authors raise IL-1 receptor antagonism as a way to get part of that effect
    pharmacologically. No patient outcome on anakinra is reported in the sources cited
    in this entry. The 2026 humanized-mouse work also bounds what this could be
    expected to do: the haematopoietic arm runs through CARD8 and caspase-1 and was not
    rescued by removing NLRP1, so IL-1 blockade is a rationale for the inflammatory arm
    rather than for the marrow failure.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: interleukin-1 receptor antagonist therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: IL-1-Driven Cutaneous and Systemic Inflammation
    treatment_effect: INHIBITS
    description: >-
      Blocking the IL-1 receptor targets the effector node the animal rescues act on.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "it raises the possibility that even partial inhibition of the NLRP1-inflammasome pathway, with IL-1Ra (anakinra) for example, would provide some therapeutic benefit for DPP9 deficient patients"
    explanation: >-
      The authors' proposal, quoted with its hedge intact. It is a mechanism-based
      rationale drawn from mouse genetics, not a reported patient response.
  - reference: PMID:42741941
    reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of CARD8 or CASP1 rescued cytopenia and loss of DPP9-deficient bone marrow stem cells, whereas NLRP1 deficiency did not."
    explanation: >-
      Cuts against the NLRP1/IL-1 rationale for the haematological phenotype
      specifically: the arm that produces the cytopenia was not rescued by removing
      NLRP1. It does not bear on the cutaneous arm.
animal_models:
- name: Dpp9 S759A catalytically inactive knock-in mouse
  species: Mouse
  genotype: Dpp9 S759A homozygous knock-in (catalytically inactive DPP9)
  publication: PMID:36112693
  description: >-
    The model that established the inflammasome dependence of DPP9 deficiency in vivo.
    Homozygotes die within a day of birth, and that lethality is rescued by removing a
    single copy of Nlrp1a/b/c, Asc, Gsdmd or Il-1r - but not Il-18. It does not model
    the human blood phenotype: mutant mice have no significant haematological
    abnormality.
  modeled_mechanisms:
  - target: IL-1-Driven Cutaneous and Systemic Inflammation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The genetic rescue series is the strongest available evidence that IL-1 receptor
      signalling downstream of the NLRP1 inflammasome is the limiting effector of DPP9
      deficiency in a whole animal.
    limitations: >-
      Mouse Nlrp1 paralogues are not the human sensor, and the readout rescued is
      neonatal lethality rather than any feature of the human disease.
    evidence:
    - reference: PMID:36112693
      reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice."
      explanation: >-
        The rescue series that grounds this link, including the negative result for
        Il-18.
  - target: Bone Marrow Stem and Progenitor Depletion
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The mouse does not develop the cytopenia that defines the human disease.
    limitations: >-
      Mice have no CARD8 gene at all, so the sensor that drives human HSPC pyroptosis is
      absent from the model by construction. No refinement of a conventional mouse model
      can recover this arm.
    evidence:
    - reference: PMID:36112693
      reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, we do not observe significant haematological abnormalities similar to those observed in patients with germline loss of DPP9 activity."
      explanation: >-
        The explicit negative result, which is what this link asserts: the model does
        not reproduce the patients' haematological phenotype. The quote is a negative
        finding about the mouse and a positive one about the failure-to-recapitulate
        claim it is attached to.
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Given that CARD8 is absent from the mouse genome yet highly enriched in human hematopoietic cell populations, we propose that the mouse-human discrepancy in DPP9 deficiency reflects a fundamentally distinct inflammasome logic governing human blood stem cell survival, one in which CARD8 serves as a sentinel whose unchecked activation is sufficient to collapse human hematopoiesis."
      explanation: >-
        The species difference that explains the failure, which is what makes this a
        structural limitation rather than a tuning problem.
  evidence:
  - reference: PMID:36112693
    reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dpp9S759A/S759A mice died within one day of birth through an unknown mechanism."
    explanation: >-
      The baseline phenotype of the model, against which every rescue in the series is
      measured.
- name: dpp9 knockout zebrafish
  species: Zebrafish
  genotype: dpp9 knockout
  publication: PMID:36112693
  description: >-
    An independent model organism giving the same answer on the inflammasome adaptor:
    inactivating asc partially rescues the lethality of dpp9 deficiency.
  modeled_mechanisms:
  - target: IL-1-Driven Cutaneous and Systemic Inflammation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Corroborates ASC dependence in a second species, which is why the inflammasome
      reading of DPP9 deficiency does not rest on mouse genetics alone.
    limitations: >-
      The rescue is partial, the readout is survival rather than inflammation, and
      zebrafish inflammasome sensors are more distant from human NLRP1 than the mouse
      paralogues are.
    evidence:
    - reference: PMID:36112693
      reference_title: "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish."
      explanation: >-
        The rescue, with the partial qualifier the source states.
experimental_models:
- name: MISTRG6 humanized mice engrafted with CRISPR-edited human CD34+ HSPCs
  experimental_model_type: OTHER
  description: >-
    Not an animal model of the disease but a human-cell system read out in a mouse
    host: human CD34+ haematopoietic stem and progenitor cells are CRISPR-edited to
    delete DPP9 and engrafted into MISTRG6 mice. Because the cells under study are
    human, the CARD8 sensor that mice lack is present, and the arm no conventional
    mouse model can show becomes visible. Deleting CARD8 or CASP1 rescued the cells;
    deleting NLRP1 did not.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:42741941
  modeled_mechanisms:
  - target: Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The system in which this node was demonstrated, in the human cell type the node
      names.
    limitations: >-
      An engineered deletion in edited cells rather than a patient genotype, and an
      engraftment setting in which transplantation stress may itself be the trigger the
      authors could not identify. The skin and neurodevelopmental arms of the disease
      are outside what an HSPC system can address.
    readouts:
    - name: Lactate dehydrogenase release from cultured HSPCs
      target: Caspase-1-Dependent Pyroptosis of Hematopoietic Stem and Progenitor Cells
      direction: ABOLISHED
      interpretation: >-
        Pyroptotic membrane rupture, abolished when CARD8 or CASP1 is deleted.
      evidence:
      - reference: PMID:42741941
        reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Pyroptosis was completely abrogated in HSPCs that lacked CARD8 or CASP1, suggesting that HSPCs undergo CARD8-dependent pyroptosis (Figure 5A)."
        explanation: >-
          The measurement and its direction under the rescue genotypes.
    evidence:
    - reference: PMID:42741941
      reference_title: "Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic."
      explanation: >-
        Establishes that the system reproduces the human phenotype it is being used to
        explain.
discussions:
- discussion_id: hatis_model_coverage_gap
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does any tractable model of this disease cover the skin and neurodevelopmental
    arms, given that the mouse lacks CARD8 and the humanized system contains only
    haematopoietic cells?
  attaches_to:
  - pathophysiology#CARD8 Inflammasome Activation in Hematopoietic Progenitors
  - phenotypes#Specific learning disability
  - phenotypes#Delayed speech and language development
  - phenotypes#Slurred speech
  - phenotypes#Autism spectrum disorder
  rationale: >-
    The two available in vivo models sit on opposite sides of the mechanism and
    neither spans it. Conventional Dpp9 mutant mice have the whole organism but no
    CARD8, so they cannot produce the marrow failure and cannot be used to ask what
    else the haematopoietic arm causes. The MISTRG6 system has human CARD8 but only in
    an engrafted haematopoietic compartment, so it cannot address skin, growth or
    neurodevelopment. The features with no model behind them are exactly the ones whose
    mechanism is unstated: learning disability and speech delay in three of four
    children, slurred speech and autism spectrum disorder in two each, and
    hemivertebrae in both children assessed, none of which has a demonstrated
    inflammasome route. The autism and the slurred speech are not scored in the same
    two children, so the cohort does not even offer a single neurodevelopmental
    phenotype to model. The mouse does reproduce runting and lung
    inflammation independently of NLRP1, which is a hint that DPP9 has
    inflammasome-independent roles - but it is a hint about stature, not about the
    neurodevelopmental findings.
- discussion_id: hatis_card8_trigger_unknown
  kind: KNOWLEDGE_GAP
  prompt: >-
    What triggers CARD8 in DPP9-deficient human haematopoietic stem and progenitor
    cells?
  attaches_to:
  - pathophysiology#CARD8 Inflammasome Activation in Hematopoietic Progenitors
  rationale: >-
    Loss of DPP9 removes a restraint; it does not by itself supply the signal a sensor
    responds to. The authors of the 2026 study say only that an undefined cellular
    stress during transplantation may be the trigger. Until that is identified it is
    not possible to say whether the disease is driven by chronic low-level firing or by
    episodic stress-driven bursts, and that distinction bears directly on whether a
    CARD8 or caspase-1 inhibitor would need to be given continuously or only around
    insults.
notes: >-
  Entry scope. This entry covers the autosomal recessive disease caused by biallelic
  DPP9 loss of function, which is what MONDO:0957229 and OMIM 620331 name. A
  separately reported patient with a de novo heterozygous DPP9 p.Arg252Pro variant and
  hemophagocytic-lymphohistiocytosis-like hyperinflammation (PMID:37544411) is
  deliberately not curated here. That variant acts by destabilising DPP9 in a
  dominant-negative manner, so it is monoallelic disease by a different genetic
  mechanism and with a different clinical picture; folding it in would put two
  inheritance modes under one recessive disease term and make the patient counts in
  this entry uninterpretable. It belongs in a separate entry if and when a disease term
  exists for it.

  Module conformance. No pathophysiology node declares conforms_to. The only
  inflammasome module in kb/modules is nlrp3_inflammasome_activation, whose own
  description scopes it to the two-signal NLRP3 pathway in which a priming signal
  licenses the cell and an activating danger signal triggers assembly. Neither half of
  that applies here: NLRP1 and CARD8 are FIIND-domain sensors held in a repressive DPP9
  complex, and disease follows from loss of the repressor rather than from arrival of a
  danger signal. All five current conformers to that module are genuine NLRP3 diseases.
  A FIIND-sensor inflammasome module covering the NLRP1/CARD8/DPP9 axis would be a new
  module rather than a widening of that one.

  Structured sources. No Orphanet record, no GeneReviews chapter and no ClinGen
  gene-disease validity assertion for DPP9 were found for this disease;
  just check-genereviews returns NO_CHAPTER for both GeneReviews and StatPearls. The
  absence is consistent with a disease first delineated in 2022 with six published
  patients.

  Counts, not frequencies. The frequency bands in this entry are derived from counts
  out of the four patients of the founding cohort, which is the only series with a
  per-patient clinical table. Read them as what they are: a band over four children.
  Rows scored in two of the four are FREQUENT; rows scored in three or four are
  VERY_FREQUENT. Two rows carry no frequency at all - hemivertebrae and selective
  immunodeficiency - because each was assessed in only two of the four patients, so the
  denominator is two and a band over four would be a fabrication.

  Phenotype scope. The entry carries every row of that clinical table scored positive
  in at least two of the four children. Rows scored in one child alone - thick skin,
  anhidrosis, dry skin, premature hair graying, delayed wound healing, broad forehead,
  febrile seizures, and cryptorchidism/hypospadias - are deliberately not curated as
  phenotypes of the disease. A single observation in a four-patient series does not
  distinguish a feature of the disease from a feature of that child, and several of
  these are common enough in unselected children that one instance carries no signal.
  They are recorded here so the omission reads as a decision, and each becomes
  curatable as soon as a second patient is reported with it. The infantile-eczema row
  is curated inside the Atopic dermatitis phenotype rather than beside it, for the
  reason that entry's description gives.

  Two HPO identifiers in that table are wrong, and neither was copied into this entry.
  The table prints HP:0002373 against "Broad forehead", but HP:0002373 is the febrile
  seizure term - which the same table also, correctly, prints against its own "Febrile
  seizures" row, so the identifier appears twice for two different features. It prints
  HP:0000776 against "Inguinal hernia", but HP:0000776 is congenital diaphragmatic
  hernia; the inguinal hernia term is HP:0000023, which is what this entry binds. Every
  identifier in this entry was resolved against HPO rather than read off the table, and
  the table rows are still quoted verbatim as snippets, identifiers included.

  Not curated for want of a source. Reported serum IL-1 beta and IL-18 concentrations,
  anakinra dosing and patient response, post-transplant outcomes, and gnomAD allele
  frequencies for the individual DPP9 variants are all absent from this entry. The
  deep-research report raised the first three, in each case flagging that the figure
  came from a secondary summary rather than a primary read; none was confirmable
  against a cached primary source here, and a weaker adjacent citation is not a
  substitute for the one that does not exist.
📚

References & Deep Research

References

3
PMID:36112693
DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling.
No top-level findings curated for this source.
PMID:42741941
Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
No top-level findings curated for this source.
PMID:41082409
Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Entry scope. This entry covers the autosomal recessive disease caused by biallelic DPP9 loss of function, which is what MONDO:0957229 and OMIM 620331 name. A separately reported patient with a de novo heterozygous DPP9 p.Arg252Pro variant and hemophagocytic-lymphohistiocytosis-like hyperinflammation (PMID:37544411) is deliberately not curated here. That variant acts by destabilising DPP9 in a dominant-negative manner, so it is monoallelic disease by a different genetic mechanism and with a different clinical picture; folding it in would put two inheritance modes under one recessive disease term and make the patient counts in this entry uninterpretable. It belongs in a separate entry if and when a disease term exists for it. Module conformance. No pathophysiology node declares conforms_to. The only inflammasome module in kb/modules is nlrp3_inflammasome_activation, whose own description scopes it to the two-signal NLRP3 pathway in which a priming signal licenses the cell and an activating danger signal triggers assembly. Neither half of that applies here: NLRP1 and CARD8 are FIIND-domain sensors held in a repressive DPP9 complex, and disease follows from loss of the repressor rather than from arrival of a danger signal. All five current conformers to that module are genuine NLRP3 diseases. A FIIND-sensor inflammasome module covering the NLRP1/CARD8/DPP9 axis would be a new module rather than a widening of that one. Structured sources. No Orphanet record, no GeneReviews chapter and no ClinGen gene-disease validity assertion for DPP9 were found for this disease; just check-genereviews returns NO_CHAPTER for both GeneReviews and StatPearls. The absence is consistent with a disease first delineated in 2022 with six published patients. Counts, not frequencies. The frequency bands in this entry are derived from counts out of the four patients of the founding cohort, which is the only series with a per-patient clinical table. Read them as what they are: a band over four children. Rows scored in two of the four are FREQUENT; rows scored in three or four are VERY_FREQUENT. Two rows carry no frequency at all - hemivertebrae and selective immunodeficiency - because each was assessed in only two of the four patients, so the denominator is two and a band over four would be a fabrication. Phenotype scope. The entry carries every row of that clinical table scored positive in at least two of the four children. Rows scored in one child alone - thick skin, anhidrosis, dry skin, premature hair graying, delayed wound healing, broad forehead, febrile seizures, and cryptorchidism/hypospadias - are deliberately not curated as phenotypes of the disease. A single observation in a four-patient series does not distinguish a feature of the disease from a feature of that child, and several of these are common enough in unselected children that one instance carries no signal. They are recorded here so the omission reads as a decision, and each becomes curatable as soon as a second patient is reported with it. The infantile-eczema row is curated inside the Atopic dermatitis phenotype rather than beside it, for the reason that entry's description gives. Two HPO identifiers in that table are wrong, and neither was copied into this entry. The table prints HP:0002373 against "Broad forehead", but HP:0002373 is the febrile seizure term - which the same table also, correctly, prints against its own "Febrile seizures" row, so the identifier appears twice for two different features. It prints HP:0000776 against "Inguinal hernia", but HP:0000776 is congenital diaphragmatic hernia; the inguinal hernia term is HP:0000023, which is what this entry binds. Every identifier in this entry was resolved against HPO rather than read off the table, and the table rows are still quoted verbatim as snippets, identifiers included. Not curated for want of a source. Reported serum IL-1 beta and IL-18 concentrations, anakinra dosing and patient response, post-transplant outcomes, and gnomAD allele frequencies for the individual DPP9 variants are all absent from this entry. The deep-research report raised the first three, in each case flagging that the figure came from a secondary summary rather than a primary read; none was confirmable against a cached primary source here, and a weaker adjacent citation is not a substitute for the one that does not exist.

Create: Hatipoglu_Immunodeficiency_Syndrome · 2026-09-23T20:11:27Z · View source

De novo curation of Hatipoglu immunodeficiency syndrome (MONDO:0957229, OMIM 620331), autosomal recessive DPP9 deficiency. Scope decision. The entry covers only the biallelic recessive disease. The de novo heterozygous DPP9 p.Arg252Pro dominant-negative patient with HLH-like hyperinflammation (PMID:37544411) is excluded, with the reasoning recorded in the entry notes: different inheritance mode, different genetic mechanism, and including it would make the per-patient counts in this entry uninterpretable. Pathograph. Seven nodes in a chain from the biallelic lesion through loss of DPP9 restraint on the FIIND sensors, then branching into the NLRP1/keratinocyte arm and the CARD8/HSPC arm. The CARD8 arm runs to caspase-1-dependent pyroptosis, marrow stem and progenitor depletion, and thence to the pancytopenia, anaemia and recurrent-infection phenotypes. DPP9 reaches the pathograph through a genes descriptor on the initiating lesion node. Phenotypes. Seventeen, taken from the per-patient clinical table of the founding cohort (PMID:36112693, four children from three families) plus the 2025 twin case report (PMID:41082409). Frequency bands are derived from counts out of four and the entry says so; hemivertebrae carries no frequency because it was assessed in only two patients. Module conformance. No conforms_to declared. The only inflammasome module in kb/modules is nlrp3_inflammasome_activation, whose description scopes it to the two-signal NLRP3 pathway; this disease is loss of a repressor acting on FIIND-domain sensors. Reasoning recorded in the entry notes. Deep research. falcon was requested and returned HTTP 402 (account out of credits); the run fell back to claude_code, which produced research/Hatipoglu_Immunodeficiency_Syndrome-deep-research-claude_code.md (fell_back: true, requested_provider: falcon, recorded in the report frontmatter). just preflight-dr returned WARN, not FAIL: DPP9 is mentioned 57 times and NLRP1 43 times, which is the expected mechanism partner rather than a second disease, and the report's OMIM identifier matches MONDO's. The report's reference validation was added with just validate-research-reference: 7 of 7 references resolved, 0 unresolved. The term-validation section could NOT be added: just validate-research-terms failed on all four attempts with a read timeout reaching www.ebi.ac.uk to resolve MONDO:0957229, so the committed report has no Term Validation section. Every CURIE bound in the entry was instead checked through just validate-terms, which passes, and the two new HP terms plus the MONDO and HGNC terms were resolved and cached by that run. No .citations.md sidecar was produced by the claude_code provider. Not curated for want of a source. Serum IL-1 beta and IL-18 concentrations, anakinra dosing and patient response, post-transplant outcomes, and per-variant gnomAD allele frequencies were all raised by the deep-research report, each flagged there as coming from a secondary summary rather than a primary read. None was confirmable against a cached primary source, so none is in the entry; the gap is recorded in the entry notes. Reference caches. Nine committed: the six the entry cites plus PMID:24223149, PMID:37544411 and PMID:42427515, which the deep-research report cites. Nine further caches fetched during the literature sweep were pruned because neither the entry nor the report needs them. Note the entry cites the J Clin Invest version of the humanized-mouse paper (PMID:42741941) rather than the bioRxiv preprint (PMID:42427515) the report cites, per the repo preference for the peer-reviewed version. Validation: just validate (schema, terms, references) passed with 65/65 snippets verified; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-reference-titles, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, list-gene-term-mismatches (0 findings), pytest tests/test_data.py -k Hatipoglu, and validate-disorders.

Claude Code ▸
Hatipoglu Immunodeficiency Syndrome (HATIS) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-23T19:46:54.984620

Hatipoglu Immunodeficiency Syndrome (HATIS) — Comprehensive Research Report

Executive Summary

Hatipoglu Immunodeficiency Syndrome (HATIS; OMIM #620331; MONDO:0957229; MedGen C5830439; also designated "Immunodeficiency 111," IMD111) is a recently delineated (2022) autosomal recessive inborn error of immunity caused by biallelic loss-of-function/hypomorphic variants in DPP9 (dipeptidyl peptidase 9; OMIM 608258; 19p13.3). It is a monogenic inflammasomopathy*: loss of DPP9's restraint on the NLRP1 (and, as shown mechanistically in 2026, CARD8) inflammasomes causes constitutive caspase-1 activation, IL-1β release, and pyroptotic cell death — most consequentially in hematopoietic stem/progenitor cells (HSPCs) and keratinocytes. Clinically the disease presents in early childhood with failure to thrive, short stature, pancytopenia/bone-marrow failure, recurrent bacterial and herpesviral infections, and a distinctive skin phenotype (eczema, dyspigmentation, petechiae), with variable neurodevelopmental features. It is disease-defining, ultra-rare (four patients from three families in the founding report, plus a fourth family reported in 2025), and severe — three of the first four reported patients required hematopoietic stem cell transplantation (HSCT).

1. Disease Information

Overview. HATIS is an autosomal recessive immunologic/autoinflammatory disorder of childhood onset characterized by failure to thrive, skin manifestations, pancytopenia, and susceptibility to recurrent infections, caused by biallelic (homozygous or compound heterozygous) DPP9 variants (Harapas et al., Sci Immunol 2022, PMID:36112693). It was named for the discovering clinician/family series (Hatipoğlu N., a co-author on the founding paper) following the OMIM naming convention for newly described monogenic disorders.

Key identifiers: - OMIM (phenotype): #620331 — HATIPOGLU IMMUNODEFICIENCY SYNDROME; HATIS - OMIM (gene): 608258 — DIPEPTIDYL PEPTIDASE IX; DPP9 (19p13.3) - MONDO: 0957229 - MedGen: C5830439 (UID 1841075) - Synonym: Immunodeficiency 111 (IMD111) - Gene: DPP9 (HGNC symbol DPP9; chr19:4,675,224–4,724,673, GRCh38) - No dedicated Orphanet, ICD-10/ICD-11, or GeneReviews* entry currently exists — this is expected given the disease was first described in 2022 with only a handful of published families; standard nosology resources have not yet caught up. (Source class: structured database absence, checked directly against MedGen/OMIM/Orphanet gene pages, September 2026.)

Synonyms/alternate names: HATIS; Immunodeficiency 111 (IMD111); "DPP9 deficiency" (mechanistic/functional name used interchangeably in the primary literature, e.g., Harapas et al. title "DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling").

Data provenance. All clinical characterization to date derives from aggregated case series and individual case reports (n=4 in the founding cohort, plus subsequent single-family/twin case reports) rather than large aggregated disease-level registries — this is a disease-level knowledge base built from primary literature synthesis, not from an EHR/claims aggregation resource, given its rarity and recency.

2. Etiology

Primary cause — genetic, monogenic. HATIS is caused by biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic variants in DPP9, encoding dipeptidyl peptidase 9, a serine protease that is a direct negative regulator of the NLRP1 (and CARD8) inflammasomes (PMID:36112693).

Genetic risk factors: - Consanguinity is a documented risk factor in at least 2 of the 3 founding families: Family 2 (14-year-old boy, homozygous c.2551C>T, p.Gln851Ter, consanguineous Turkish parents) and Family 3 (2 male patients, homozygous c.331C>T, p.Arg111Ter, consanguineous Bedouin family, Israel). Family 1's proband was compound heterozygous (paternal p.Gly167Ser [c.499G>A]; maternal p.Ser214Ter), consistent with a non-consanguineous mating (PMID:36112693; ClinVar RCV003224652 for c.499G>A/p.Gly167Ser). - A 2025 case report (PMID:41082409) describes 8-month-old dizygotic/monozygotic twins from a non-consanguineous marriage with biallelic DPP9 mutation, expanding the mutational/ancestral spectrum beyond the original consanguineous founder families. - No modifier genes have yet been reported for HATIS specifically, though the mouse genetic-rescue data (below) implicate the entire NLRP1→ASC→caspase-1→GSDMD→IL-1R axis as a mechanistic "modifier pathway" whose dosage determines severity.

Environmental risk factors: None established; this is a fully penetrant monogenic disease with no reported environmental gene–disease interaction data. Infections (herpesviruses, bacterial otitis/bronchitis pathogens) are a consequence of the immunodeficiency rather than a cause, though they may act as triggers/exacerbants of inflammasome flares in a susceptibility background (analogous to the de novo dominant-negative DPP9 disorder below, where infection precipitated HLH-like hyperinflammation).

Protective factors: None reported. There is no described protective allele or environmental protective factor.

Gene–environment interactions: Not established for biallelic HATIS. However, the mechanistically related monoallelic, dominant-negative DPP9 disorder (see below) shows that inflammasome-priming stimuli (e.g., infection) can precipitate acute HLH-like crises on a sensitized inflammasome-regulatory background — a plausible but unproven gene–environment interaction template for HATIS flares as well.

Important nosological distinction — do not conflate two DPP9-related conditions:

Feature HATIS (biallelic) De novo dominant-negative DPP9 disorder
Inheritance Autosomal recessive, biallelic LOF/hypomorphic Heterozygous, de novo, dominant-negative
Variant e.g., p.Gln851Ter, p.Arg111Ter, p.Gly167Ser/p.Ser214Ter c.755G>C, p.Arg252Pro
Mechanism Complete/near-complete loss of DPP9 restraint Destabilized DPP9 (26–52% WT levels) still fails to restrain NLRP1/CARD8
Phenotype Pancytopenia, failure to thrive, skin disease, recurrent infection (chronic) HLH-like hyperinflammation, massive IL-1β/IL-18, hepatosplenomegaly, fever (acute/severe infantile)
Reference Harapas et al. 2022, PMID:36112693 Wolf et al. 2023, J Allergy Clin Immunol 152(5):1336–1344.e5, PMID:37544411

This distinction should be preserved in curation — the dominant-negative disorder is a distinct clinical entity sharing the same gene and inflammasome mechanism, not a HATIS subtype, per the design-decision on keeping germline mechanism-sharing entities separate unless explicitly lumped by the field.

3. Phenotypes

Phenotype data below are drawn from the MedGen/OMIM clinical synopsis for #620331 and the Harapas et al. 2022 primary cohort (4 patients, ages 6–14 at description) plus the 2025 twin case report (PMID:41082409). Frequencies among only 4–6 published patients should be read as small-n case-series proportions, not population-level penetrance estimates — a caveat that should be preserved in any curated frequency field.

Symptoms / Clinical Signs

Phenotype Suggested HPO term Notes
Failure to thrive HP:0001508 Reported in essentially all patients (defining feature)
Fetal growth restriction HP:0001511 Prenatal onset in some patients
Proportionate short stature HP:0003508
Feeding difficulties HP:0011968
Recurrent infections HP:0002719 Defining feature
Recurrent otitis media HP:0000403
Recurrent bronchitis HP:0002837
Recurrent herpes HP:0100819 (herpetic infection context) / herpes simplex/zoster reactivation Reported in 2 of 4 founding patients
Recurrent fever HP:0001954
Febrile seizures HP:0002373
Pancytopenia HP:0001876 Core hematologic feature; drove HSCT decision in 3/4 patients
Anemia HP:0001903
Petechiae HP:0000967
Infantile eczema / atopic dermatitis HP:0001047 (Atopic dermatitis) In 2/4 patients
Eczematoid dermatitis related to HP:0000964 (Eczema)
Dry skin HP:0000958
Thickened skin HP:0008065
Anhidrosis HP:0000970
Hyper-/hypopigmented macules HP:0007440 (Hyperpigmented skin macules) / HP:0001053 (Hypopigmented skin patches) Distinctive dyspigmentation reported in all founding patients
Premature graying / fair hair HP:0002216 (Premature graying of hair)
Poor wound healing HP:0001058
Learning disability / speech delay HP:0002194 (Delayed speech and language development), HP:0001328 (Specific learning disability) 3 of 4 patients
Autism spectrum / autistic behavior HP:0000717 2 of 4 patients
Slurred speech HP:0001350
Downslanting palpebral fissures HP:0000494 2 of 4 patients
Broad forehead HP:0000337
Hemivertebrae HP:0002937 2 of 4 patients
Cryptorchidism HP:0000028
Hypospadias HP:0000047
Inguinal hernia HP:0000023
Asthma/allergy HP:0002099 (Asthma)

Phenotype characteristics

  • Age of onset: Childhood, often with prenatal (fetal growth restriction) or infantile onset of failure to thrive; the 2025 case report describes presentation at 8 months of age (twins) with severe anemia and infections.
  • Severity: Variable but often severe — 3 of the 4 founding-cohort patients ultimately required HSCT for bone marrow failure/pancytopenia.
  • Progression: Chronic and progressive marrow failure with episodic infectious/inflammatory flares; not classically relapsing-remitting but punctuated by acute infectious or inflammatory episodes.
  • Frequency (case-series, not population level): Neurodevelopmental features (learning disability/speech delay) in 3/4; autism spectrum features in 2/4; craniofacial dysmorphism (downslanting palpebral fissures) in 2/4; hemivertebrae in 2/4 — small numbers, interpret cautiously.
  • Quality of life impact: Not formally measured with validated instruments (EQ-5D, SF-36) in the literature to date; qualitatively, recurrent hospitalization for infection/transfusion (documented explicitly in the 2025 twin case, PMID:41082409: "recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions") and HSCT burden indicate substantial disease impact, but no formal QoL instrument data exist — this is a genuine evidence gap, not merely unreported.

4. Genetic/Molecular Information

Causal gene: DPP9 (dipeptidyl peptidase 9), HGNC symbol DPP9, OMIM *608258, chromosome 19p13.3 (GRCh38 chr19:4,675,224–4,724,673). Ubiquitously expressed with highest levels in liver, heart, and muscle, lowest in brain (per GeneCards/OMIM gene summary).

Protein: 863 amino acids, ~98 kDa, containing an active-site serine protease motif (GWSYG, post-proline dipeptidyl aminopeptidase activity cleaving Xaa-Pro dipeptides from protein N-termini) and 2 N-glycosylation sites. DPP9 is cytosolic (unlike its membrane-bound relative DPP4/CD26) and is a member of the S9B prolyl oligopeptidase family together with DPP8.

Reported pathogenic variants (biallelic HATIS):

Family Genotype Variant(s) Consequence Consanguinity
1 Compound heterozygous c.499G>A (p.Gly167Ser, paternal) / p.Ser214Ter (maternal) Missense (hypomorphic) / nonsense Not stated as consanguineous
2 Homozygous c.2551C>T (p.Gln851Ter) Nonsense, exon 21; absent DPP9 protein on patient fibroblast Western blot, consistent with nonsense-mediated decay → complete loss of function Consanguineous (Turkish)
3 (2 affected males) Homozygous c.331C>T (p.Arg111Ter) Nonsense, exon 5 Consanguineous (Bedouin, Israel)
2025 twin case Biallelic (specific alleles not extracted from abstract) Not detailed in available abstract — Non-consanguineous

Source: Harapas et al., Sci Immunol 2022 (PMID:36112693); ClinVar RCV003224652 for p.Gly167Ser; Singh et al. 2025 (PMID:41082409).

Variant classification / functional impact: The Harapas et al. paper functionally characterized these variants as hypomorphic or loss-of-function alleles that fail to repress NLRP1 — i.e., FunctionalImpactEnum = LOSS_OF_FUNCTION (nonsense alleles p.Gln851Ter, p.Arg111Ter, p.Ser214Ter) or PARTIAL_LOSS_OF_FUNCTION/hypomorphic (missense p.Gly167Ser). ACMG/AMP classification per ClinVar for p.Gly167Ser should be checked directly in ClinVar at curation time rather than assumed.

Allele frequency: Not reported in the primary literature abstracts retrieved; given the extreme rarity (four families worldwide as of the founding report, one additional twin case since), these variants are expected to be private/family-specific or extremely rare in gnomAD — this should be verified directly against gnomAD at curation time rather than asserted from memory (per this repository's Ontology Term Contract, the same "never write from memory" discipline extends to any quantitative claim not directly sourced).

Somatic vs. germline: All reported HATIS variants are germline.

Contrast — the dominant-negative variant: c.755G>C (p.Arg252Pro), heterozygous, de novo, in the distinct HLH-like hyperinflammatory disorder (PMID:37544411). This variant destabilizes the DPP9 protein (reducing expression to ~26–52% of wild-type in transfected cells) such that the mutant protein "failed to restrain the NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation" — a dominant-negative mechanism, mechanistically and clinically distinct from the biallelic loss-of-function/hypomorphic HATIS variants.

Modifier genes: None specifically implicated in HATIS patients, but functional/genetic-rescue data in animal models (see Mechanism, below) show that Nlrp1a/b/c, Asc (Pycard), Gsdmd, Il-1r, and — in the humanized mouse — CARD8/CASP1 are all dosage-sensitive modifiers of the phenotype, making them plausible candidate modifier loci for human disease severity, though this is inferred from model systems and not yet demonstrated in patients.

Epigenetic information: None reported for HATIS.

Chromosomal abnormalities: None; this is a point-mutation/small-indel disorder, not a copy-number or structural disorder.

5. Environmental Information

HATIS is a monogenic disorder with no established primary environmental etiologic factor. The clinically relevant "environmental" contributors are infectious triggers of disease flares/complications rather than causes of the underlying disease: - Infectious agents documented in patients: herpesviruses (recurrent herpetic infections), otitis-media pathogens, and bronchitis-associated respiratory pathogens — these represent the consequence of impaired immune competence (recurrent infection susceptibility) but, per the mechanistically related dominant-negative DPP9 disorder, infection may also act as a trigger that precipitates acute inflammasome-driven hyperinflammatory flares on top of chronic immunodeficiency. No specific pathogen has been identified as a required precipitant for HATIS-specific inflammasome flares (as distinct from the HLH-like disorder). - Lifestyle/toxin/occupational factors: None reported; disease onset is in infancy/early childhood, prior to occupational exposure windows.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function or hypomorphic variants in DPP9 (e.g., p.Gln851Ter, p.Arg111Ter, p.Gly167Ser/p.Ser214Ter) → loss (or severe reduction) of DPP9 dipeptidyl peptidase/scaffolding activity in patient cells (demonstrated directly: patient fibroblasts from Family 2 showed absent DPP9 protein by Western blot, PMID:36112693).
  2. Loss of DPP9 → failure to form the inhibitory DPP9–NLRP1(FIIND)–NLRP1(C-terminal UPA-CARD fragment) ternary complex that normally sequesters the autoproteolytically-generated NLRP1 C-terminal fragment in an inactive state (mechanism established in Nature 2021, PMID for "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation," and corroborating structural/biochemical studies of the FIIND ZU5-UPA autoproteolysis and "functional degradation"/N-end-rule model of NLRP1 activation).
  3. Loss of ternary-complex sequestration → the NLRP1 C-terminal UPA-CARD fragment is liberated from autoinhibition and free to oligomerize, and — as shown by direct reverse-genetics evidence in a 2026 humanized-mouse study — the CARD8 inflammasome is analogously de-repressed in human hematopoietic cells (PMID:42427515/JCI 10.1172/JCI207530). This is the key human-specific branch point: mouse Dpp9 loss activates NLRP1 but (because mice lack a functional CARD8) does not recapitulate the CARD8-driven hematopoietic phenotype, explaining why constitutive Dpp9-knockout mice have grossly normal hematopoiesis despite recapitulating other aspects of disease.
  4. Liberated NLRP1 (skin, epithelial tissue) and CARD8 (human hematopoietic stem/progenitor cells, HSPCs — CARD8 is "absent from the mouse genome yet highly enriched in human hematopoietic cell populations," per the 2026 JCI study) assemble into an active inflammasome complex recruiting ASC (in the NLRP1 branch) and activating caspase-1.
  5. Caspase-1 activation → (a) cleavage and activation of gasdermin D (GSDMD), driving pyroptotic cell death, and (b) proteolytic maturation and release of IL-1β (and, to a lesser/dispensable extent based on murine rescue data, IL-18).
  6. In HSPCs, CARD8-inflammasome-driven pyroptosis (demonstrated by CASP1/CARD8 genetic deletion rescuing cytopenia and HSPC survival in the humanized mouse model, while NLRP1 deletion did not) causes direct destruction of the hematopoietic stem/progenitor pool → bone marrow failure, pancytopenia, and anemia — the dominant, treatment-defining clinical feature requiring HSCT in most reported patients.
  7. In keratinocytes and skin, spontaneous NLRP1 inflammasome activation (directly demonstrated ex vivo in patient keratinocytes, PMID:36112693) drives IL-1β-mediated cutaneous inflammation, manifesting as eczema/dermatitis, petechiae (from combined thrombocytopenia and vascular inflammation), and pigmentary change.
  8. Chronic systemic low-grade inflammasome activation plus loss of the immune cell compartments that depend on intact hematopoiesis (neutrophils, lymphocytes) together produce failure to thrive/growth restriction and immunodeficiency with recurrent bacterial and herpesviral infection — the latter reflecting depletion of both innate (neutrophil) and adaptive (T/B/NK) effector populations secondary to marrow failure, compounding any cell-intrinsic lymphocyte inflammasome dysregulation.
  9. Neurodevelopmental and skeletal features (learning disability, autism-spectrum features, hemivertebrae, craniofacial dysmorphism) are reported in a subset of patients; a direct causal inflammasome mechanism for these specific features has not been mechanistically demonstrated in the literature reviewed and should be treated as an associated but mechanistically unresolved part of the phenotype (a candidate HUMAN_MODEL_MISMATCH/knowledge-gap discussion point for curation, since animal models do not obviously recapitulate this branch).

Molecular pathways

  • NLRP1 inflammasome pathway (canonical activation via FIIND autoproteolysis + N-end-rule/functional degradation model): GO:0140639 (NLRP1 inflammasome complex) / relevant GO biological process terms for "positive regulation of NLRP1 inflammasome complex assembly."
  • CARD8 inflammasome pathway (human-specific, hematopoietic-restricted) — mechanistically analogous FIIND-domain regulation by DPP9.
  • Pyroptosis — GO:0070269 (pyroptotic cell death; gasdermin D pore formation).
  • IL-1β maturation/signaling — caspase-1-dependent pro-IL-1β cleavage; IL-1R signaling.

Cellular processes

  • Pyroptosis (GSDMD-mediated), inflammatory cytokine release (IL-1β predominant; IL-18 dispensable per murine genetic-rescue data), keratinocyte-intrinsic inflammasome activation, hematopoietic stem/progenitor cell death.

Protein dysfunction

  • DPP9 loss of scaffolding/enzymatic function → derepression (not "gain of function" of a pathway per se, but qualitative loss of restraint) of NLRP1/CARD8 — this is the canonical LOSS_OF_FUNCTION variant-level annotation on GeneticContext, with the downstream pathway node itself appropriately annotated GAIN_OF_FUNCTION/INCREASED (inflammasome activity) as a pathway-state modifier, since the pathway activation is qualitatively unconstrained rather than merely quantitatively elevated above a normally-regulated baseline.

Tissue damage mechanisms

  • Direct pyroptotic destruction of HSPCs (bone marrow failure) and likely of keratinocytes/skin-resident cells (dermatitis, petechiae via vascular/platelet involvement).

Cell types involved (suggested CL terms)

  • Hematopoietic stem cell (CL:0000037)
  • Hematopoietic multipotent progenitor cell (CL:0000048)
  • Keratinocyte (CL:0000312)
  • Neutrophil (CL:0000775) — secondarily depleted
  • T cell (CL:0000084), B cell (CL:0000236), NK cell (CL:0000623) — secondarily depleted, per patient immunophenotyping showing "markedly reduced neutrophils and T/B/NK cells" in the related dominant-negative disorder (PMID:37544411) and pancytopenia in HATIS itself.

Molecular profiling / advanced technologies

  • The 2026 JCI reverse-genetics study (PMID:42427515) used a humanized mouse model (MISTRG6) engrafted with human HSPCs to demonstrate that "DPP9 deletion led to little transcriptional changes, suggesting post-transcriptional regulation in human HSPCs" — i.e., transcriptomic profiling was performed and was uninformative/negative, with the causal mechanism instead resolved by targeted genetic epistasis (CARD8/CASP1 knockout rescue) rather than by expression-based discovery. This is a useful analyses provenance note: transcriptomics was attempted (SUCCEEDED as an assay, but essentially a negative/non-explanatory result) and the definitive mechanistic claim rests on CRISPR-based reverse genetics in the humanized model, not on omics.

7. Anatomical Structures Affected

Organ level: - Primary: Bone marrow/hematopoietic system (pancytopenia, marrow failure), skin/integument (eczema, dyspigmentation, petechiae, anhidrosis), immune system broadly (recurrent infection). - Secondary/complication-driven: Respiratory system (recurrent bronchitis, sino-pulmonary infection in the twin case), ENT (recurrent otitis media), reproductive/genitourinary (cryptorchidism, hypospadias — reported in a subset), musculoskeletal (hemivertebrae), CNS/neurodevelopmental (learning disability, speech delay, autism-spectrum features). - Body systems: Hematologic/immune (primary), integumentary (primary), musculoskeletal, genitourinary, nervous system (secondary/associated).

Tissue/cell level: Bone marrow stroma and hematopoietic stem/progenitor compartment (CL:0000037); epidermal keratinocytes (CL:0000312); circulating leukocyte lineages (neutrophils, T/B/NK cells) reduced secondary to marrow failure.

Subcellular level: Cytosolic — DPP9 is a cytosolic serine protease (unlike membrane-bound DPP4); the NLRP1/CARD8 inflammasome complex it regulates assembles in the cytoplasm (GO cellular component: cytosol, GO:0005829; inflammasome complex, GO:0061702).

Localization: Bilateral/systemic — no lateralization reported; skin findings and marrow failure are systemic/diffuse rather than focal.

Suggested UBERON terms: bone marrow (UBERON:0002371), skin epidermis (UBERON:0001003), hematopoietic system (UBERON:0002390).

8. Temporal Development

  • Onset: Childhood, with evidence of onset as early as the prenatal period (fetal growth restriction reported) and presentation in infancy (the 2025 twin case presented at 8 months of age). The founding cohort patients were characterized at ages 6–14 years, reflecting diagnostic delay typical of an ultra-rare, only-recently-molecularly-defined disease rather than true late onset.
  • Onset pattern: Insidious/chronic (failure to thrive, growth restriction, progressive cytopenia) punctuated by acute infectious/febrile episodes.
  • Progression: Progressive bone marrow failure culminating in need for HSCT in the majority of reported patients (3 of 4 founding-cohort patients); disease course otherwise chronic with recurrent infectious and dermatologic flares rather than a discrete staged progression model (no formal staging system exists, as expected for an ultra-rare monogenic disorder).
  • Disease course pattern: Chronic with superimposed acute infectious/inflammatory episodes; not classically relapsing-remitting in the autoimmune sense, though marrow failure severity and infection frequency vary over time.
  • Duration: Chronic, lifelong absent curative intervention (HSCT); no reports of spontaneous resolution.
  • Remission: No spontaneous remission reported; HSCT is reported as a disease-modifying/curative intervention for the hematologic phenotype in the patients who received it (specific post-HSCT outcome/survival data were not extracted in full from the abstracts reviewed and should be verified against full text at curation time).
  • Critical periods: Early recognition and consideration of HSCT before life-threatening cytopenia/infection appears to be the key intervention window, based on the pattern of eventual bone marrow transplantation in most reported cases (inference from case pattern, not a formally stated "critical period" in the literature).

9. Inheritance and Population

Epidemiology: HATIS is ultra-rare — the founding description (2022) reported only 4 patients from 3 unrelated families; a subsequent 2025 case report added twin siblings from a fourth, non-consanguineous family. No formal prevalence or incidence estimate exists in Orphanet, GBD, or national registries (expected/appropriate given fewer than 10 published cases as of this report). Any curated Prevalence record should use measure_type: CASES_IN_LITERATURE and prevalence_class: NOT_YET_DOCUMENTED rather than inventing a numeric estimate.

Inheritance pattern: Autosomal recessive (biallelic DPP9 variants required for HATIS). The mechanistically related but clinically distinct hyperinflammatory disorder is autosomal dominant/de novo (heterozygous dominant-negative) — see the nosological distinction table in Section 2. Do not conflate the two inheritance patterns under one entry.

Penetrance: Appears fully penetrant among biallelic carriers in the reported families (all reported biallelic individuals were symptomatic), though the numerator (n≈6 published cases) is far too small to formally estimate penetrance with confidence.

Expressivity: Variable — e.g., neurodevelopmental features (autism-spectrum, learning disability), skeletal anomalies (hemivertebrae), and facial dysmorphism were present in some but not all founding-cohort patients despite presumably similarly severe loss-of-function genotypes, indicating variable expressivity of the extra-hematologic/extra-cutaneous phenotype.

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not reported.

Founder effects: Not established; the four founding families are geographically/ethnically diverse (unspecified/Australian-ascertained Family 1, Turkish consanguineous Family 2, Bedouin-Israeli consanguineous Family 3), arguing against a single founder allele, though each family's specific variant may be a local founder allele within its population — this has not been formally tested.

Consanguinity role: Documented in 2 of the first 3 families (Families 2 and 3), consistent with the expected enrichment of rare autosomal recessive disease in consanguineous unions; however, the twin case (2025) and Family 1 (compound heterozygous) demonstrate the disease also occurs in non-consanguineous settings.

Carrier frequency: Not established/reported; given the extreme rarity and apparent allelic heterogeneity (distinct private variants in each family), no meaningful population carrier frequency can currently be stated — verify directly against gnomAD allele counts for each specific variant at curation time rather than inferring a population-level carrier rate.

Population demographics: Reported cases span Australian (ascertainment center), Turkish, Bedouin-Israeli, and unspecified additional (2025 twin case) ancestries — no single ethnic group appears preferentially affected based on current (extremely limited) case numbers.

Sex ratio: Of the founding cohort, at least 3 of 4 reported patients are described as male (Family 2's single patient and Family 3's two patients are explicitly male); Family 1's proband's sex was not specified in the sources reviewed. This is too small a sample to establish a true sex ratio, and no biological (e.g., X-linked modifier) basis for male predominance has been proposed — treat as an observation, not an established epidemiological sex ratio.

Age distribution: All reported patients are pediatric at diagnosis (infancy through mid-adolescence); no adult-onset or adult-diagnosed cases have been reported, consistent with the severity of the hematologic phenotype necessitating early clinical attention.

10. Diagnostics

Laboratory tests: - Complete blood count showing pancytopenia/anemia (core finding). - Inflammatory marker elevation (in the mechanistically related dominant-negative disorder: elevated LDH, ferritin, soluble IL-2 receptor, triglycerides, and "massively increased" serum IL-1β and IL-18 — PMID:37544411; analogous but generally less extreme inflammatory marker elevation is expected in classic biallelic HATIS, though this should be confirmed per-patient rather than assumed to be identical to the dominant-negative phenotype). - Immunophenotyping showing reduced neutrophils and T/B/NK lymphocyte populations. - Dihydrorhodamine (DHR) test: in the 2025 twin case, DHR testing was positive, initially suggestive of chronic granulomatous disease, until whole-exome sequencing redirected the diagnosis to DPP9 mutation — an important differential-diagnosis pitfall worth noting for diagnostic-criteria curation (DHR abnormalities are not specific to CGD and can occur in other neutrophil-affecting immunodeficiencies).

Genetic testing: Whole-exome sequencing (WES) was the diagnostic modality in all reported cases (founding cohort and 2025 twin case). No dedicated commercial gene panel or GTR-listed single-gene test was identified in the sources reviewed; given the disease's recent molecular delineation (2022), it is most likely to be diagnosed via WES/WGS with subsequent identification of biallelic DPP9 variants, rather than via a targeted panel — clinicians should ensure DPP9 is included in relevant primary immunodeficiency/bone-marrow-failure/autoinflammatory gene panels going forward.

Functional/research-level confirmation used in the literature (not yet routine clinical tests): - Western blot for DPP9 protein in patient fibroblasts (confirmed absent protein in the Gln851Ter homozygote, supporting nonsense-mediated decay/complete loss of function). - Ex vivo keratinocyte inflammasome activation assays (spontaneous NLRP1 activation demonstrated in patient keratinocytes). - Serum IL-1β/IL-18 measurement as a research-level functional readout of inflammasome activity.

Imaging/other: No disease-specific imaging protocol reported; skeletal imaging may reveal hemivertebrae as an incidental/associated finding.

Differential diagnosis: Other inborn errors of immunity presenting with bone marrow failure and recurrent infection (e.g., Fanconi anemia, dyskeratosis congenita, GATA2 deficiency, severe combined immunodeficiency variants), other monogenic autoinflammatory/inflammasomopathy disorders (NLRP1-associated autoinflammation with arthritis and dyskeratosis [NAIAD], CARD8-related disease), and — critically, per the 2025 case — chronic granulomatous disease (given a false-suggestive positive DHR test in at least one reported case).

Screening: No newborn screening or population carrier-screening program exists for this ultra-rare, only-recently-described disorder.

11. Outcome / Prognosis

Survival/mortality: No formal survival statistics (5-year/10-year survival rates) exist given the extremely small published cohort; outcome data are anecdotal/case-level. Three of the four founding-cohort patients required HSCT for bone marrow failure, implying that without transplantation the hematologic phenotype is life-threatening; specific post-HSCT survival/engraftment outcomes were not fully extracted from the abstracts reviewed here and should be confirmed against full text before use in a curated Outcome/Prognosis field — do not assert a specific survival percentage without direct verification.

Morbidity: Substantial — recurrent infection requiring hospitalization, recurrent transfusion dependence (explicitly described in the 2025 twin case: "recurrent sino-pulmonary infections requiring multiple hospitalizations and blood transfusions," PMID:41082409), chronic skin disease, and in a subset, neurodevelopmental impairment (learning disability, autism-spectrum features) with associated long-term functional impact.

Quality of life: No validated QoL instrument data reported — genuine gap, not merely unreported detail.

Complications: Bone marrow failure/pancytopenia (primary complication driving HSCT), recurrent/severe infections (bacterial, herpesviral), transfusion-related complications (implied by transfusion dependence), and potential HSCT-related morbidity (not itself disease-specific but a consequence of the required intervention).

Recovery potential: HSCT is reported as the definitive intervention for the hematologic phenotype in patients who progress to bone marrow failure; whether HSCT also modifies the extra-hematologic (skin, neurodevelopmental) phenotype is not established in the sources reviewed.

Prognostic factors: Not formally modeled; qualitatively, severity of pancytopenia appears to be the key driver of need for HSCT.

12. Treatment

Pharmacotherapy: - IL-1 blockade (anakinra) has been attempted clinically. In one reported case, anakinra (2–4 mg/kg/day) over one week was ineffective, and following a subsequent inflammatory flare with elevated proinflammatory cytokines, the clinical team proceeded to allogeneic HSCT (source: search synthesis of case-report literature; this specific dosing/outcome detail should be re-verified against the primary full-text source before being entered as a curated evidence snippet, since it was obtained via a secondary AI-generated search summary rather than direct abstract text in this session — flagged here explicitly per this repository's attribution discipline). - Suggested NCIT term for anakinra as a therapeutic agent: NCIT (IL-1 receptor antagonist) — CHEBI term for anakinra itself should be looked up directly (CHEBI ID not verified in this session). - Preclinically, genetic (not yet pharmacologic) lowering of NLRP1/IL-1 signaling rescues murine and zebrafish phenotypes (Harapas et al. 2022): removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r — but notably not Il-18 — rescued the lethal/pathologic phenotype in the Dpp9 catalytically-inactive (S729A) mouse model, and asc knockout rescued survival of dpp9-knockout zebrafish. This provides strong preclinical rationale for IL-1-pathway-targeted therapy (anakinra, canakinumab, or NLRP1-inflammasome-directed agents as they become available) as a rational, mechanism-matched treatment strategy, even though clinical experience so far (single reported case) suggests anakinra alone may be insufficient once the hematologic phenotype has manifested — possibly because the dominant hematopoietic pathology in humans is CARD8-driven (IL-1-independent at the level of pyroptotic HSPC death) rather than purely NLRP1/IL-1-driven, per the 2026 mechanistic study. This is an important treatment-rationale nuance: CARD8/caspase-1-targeted strategies, not only IL-1 blockade, may be needed to address the marrow-failure component, since genetic CASP1 or CARD8 (but not NLRP1) deletion rescued HSPC survival in the human-relevant humanized mouse model (PMID:42427515).

Advanced therapeutics: - Hematopoietic stem cell transplantation (allogeneic HSCT): the primary disease-modifying intervention reported to date, used in 3 of the first 4 published patients and in at least one additional reported case following anakinra failure. NCIT term: NCIT:C15431 (Hematopoietic Cell Transplantation). - No gene therapy, gene editing, RNA-based therapy, or targeted small-molecule NLRP1/CARD8 inhibitor has been reported in HATIS patients to date (research-stage NLRP1/CARD8/caspase-1 inhibitors exist in the broader inflammasome field but are not reported as used in this specific disease).

Supportive care: Transfusion support (red cell/platelet, per the twin case report), management of recurrent infections (antimicrobial therapy for bacterial otitis/bronchitis, antiviral therapy for herpetic infections), and dermatologic management of eczema/atopic dermatitis (standard topical/systemic eczema management, not disease-specific).

Experimental/clinical trials: No disease-specific registered clinical trial (ClinicalTrials.gov NCT) was identified for HATIS in the searches performed in this session — expected given the extreme rarity of the condition; this should be explicitly re-checked at curation time via just fetch-reference/ClinicalTrials.gov search rather than assumed absent purely on the basis of this session's search results.

Treatment outcomes: Insufficient published data to characterize formal response rates; anakinra failure and progression to HSCT is described in at least one case.

Treatment strategy / personalized medicine: The emerging mechanistic distinction between NLRP1-driven skin/epithelial pathology (rescuable by IL-1 blockade in principle) and CARD8-driven, IL-1-independent HSPC pyroptosis (rescuable by CASP1/CARD8 inhibition, not by IL-1 blockade) suggests that future genotype- and mechanism-guided therapy may need to combine IL-1-pathway blockade (for cutaneous/systemic inflammation) with CARD8/caspase-1-targeted strategies or early HSCT (for marrow failure) — this is a reasoned mechanistic inference from the 2026 JCI paper's genetic-rescue data, not yet a clinically validated treatment algorithm, and should be labeled as such in any curated mechanistic_hypotheses block.

13. Prevention

Primary prevention: None available — this is a fully penetrant monogenic recessive disorder; primary prevention is limited to genetic counseling and reproductive options (carrier testing of parents/relatives in known-affected families, prenatal diagnosis, preimplantation genetic diagnosis) once a family's causal variant is known — standard practice for any newly delineated autosomal recessive Mendelian disorder, though not specifically reported as implemented for HATIS in the literature reviewed.

Secondary prevention: Early recognition (WES-based diagnosis) to enable timely consideration of HSCT before life-threatening cytopenia/infection develops appears to be the de facto secondary-prevention strategy emerging from the case pattern, though no formal screening program exists.

Tertiary prevention: Infection prophylaxis (e.g., antimicrobial prophylaxis, IVIG if indicated by humoral immune status) in patients with established pancytopenia/immunodeficiency — standard supportive practice for immunodeficient patients generally, not specifically validated for HATIS.

Immunization: Not specifically addressed in the literature reviewed; live vaccines would be expected to be contraindicated in the context of significant lymphopenia/immunodeficiency, following general primary-immunodeficiency vaccination principles, though this is an inference rather than a disease-specific published recommendation.

Genetic counseling: Recommended given autosomal recessive inheritance with 25% recurrence risk per pregnancy for parents of an affected child; consanguinity counseling relevant in at least 2 of the 3 founding families.

Public health/environmental interventions: Not applicable (not an environmentally modifiable disease).

14. Other Species / Natural Disease

Naturally occurring disease in other species: None reported. No spontaneous/naturally occurring DPP9-deficiency disease has been described in companion animals, livestock, or wildlife in the sources reviewed (no OMIA entry identified). All non-human DPP9-deficiency phenotypes described in the literature are induced/engineered models (see Section 15), not naturally occurring veterinary disease — this should be recorded as an explicit "no natural animal disease identified" rather than left silently blank.

Orthologous gene: Mouse Dpp9 (MGI ortholog of human DPP9) is well characterized functionally; no OMIA or comparable veterinary-disease cross-reference exists.

Zoonotic potential / cross-species susceptibility: Not applicable — this is a monogenic host-genetic disorder, not an infectious/transmissible disease.

15. Model Organisms

Mouse models (genetic, induced): - Dpp9 constitutive knockout mice: Neonatal lethal due to a suckling defect related to migratory tongue muscle progenitor survival (PMID:24223149/PMC3819388 lineage of work; ScienceDirect developmental-biology paper on DPP9 enzyme activity and tongue muscle progenitors) — this model demonstrates an essential non-hematopoietic developmental role for DPP9 enzymatic activity distinct from the human hematologic phenotype, and notably does not recapitulate human pancytopenia ("Dpp9 mutant mice have normal hematopoiesis," per PMID:42427515), making this an instructive human–model mismatch for the bone-marrow-failure phenotype specifically. - Dpp9-S729A knock-in mice (catalytically inactive DPP9, serine-to-alanine active-site point mutation): Homozygotes are born alive but die within 8–24 hours of birth (no weaned homozygotes recovered), modeling the catalytic-loss aspect of human disease. Genetic rescue experiments in this model directly established the NLRP1-dependence of lethality: removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r (but not Il-18) rescued the lethal phenotype, providing the foundational genetic evidence that NLRP1-inflammasome/IL-1 (not IL-18) signaling drives DPP9-deficiency pathology in this model (PMID:36112693). - MISTRG6 humanized mice engrafted with human HSPCs (Xiao et al., PMID:42427515/JCI 10.1172/JCI207530, 2026): A reverse-genetics human-relevant model specifically constructed to address the mouse–human discrepancy in hematopoietic phenotype. In this model, DPP9 deletion in human HSPCs activated the CARD8 inflammasome (a gene absent from the mouse genome), causing HSPC pyroptosis; NLRP1 was dispensable for this cell death, and CARD8 or CASP1 deletion rescued cytopenia and HSPC survival, whereas NLRP1 deficiency did not. This is the most direct and translationally important model to date, explaining why prior mouse models failed to recapitulate the defining human hematologic phenotype and providing a validated system for future therapeutic testing (e.g., of CARD8/caspase-1-directed agents).

Zebrafish models: - dpp9 knockout zebrafish: Recapitulate lethality; genetic knockout of asc (the inflammasome adaptor) rescues survival, corroborating the NLRP1(ASC)-dependence of pathology across two independent model systems (mouse and zebrafish) (PMID:36112693).

Cellular/in vitro models: - Patient-derived fibroblasts (Western blot confirming absent DPP9 protein in the Gln851Ter homozygote — direct human cellular evidence of complete loss of function). - Patient-derived keratinocytes (ex vivo demonstration of spontaneous NLRP1 inflammasome activation, directly linking the cutaneous phenotype to the proposed mechanism in human cells, not merely inferred from mouse skin). - Transfection-based studies of the dominant-negative p.Arg252Pro variant (distinct disorder) quantifying reduced DPP9 protein stability (26–52% of wild-type).

Model recapitulation summary (fidelity assessment for curation):

Model Recapitulates Fails to recapitulate / limitation
Constitutive Dpp9-KO mouse Neonatal lethality (via tongue-muscle mechanism) Normal hematopoiesis — does NOT model human pancytopenia (species-specific CARD8 absence)
Dpp9-S729A knock-in mouse NLRP1/ASC/GSDMD/IL-1R-dependent lethality; genetic rescue logic Still does not model human marrow-failure mechanism (no CARD8)
Zebrafish dpp9-KO ASC-dependent lethality Distant species; hematopoietic-specificity not the focus
MISTRG6 humanized mouse + human HSPCs CARD8-dependent human HSPC pyroptosis — the defining human hematologic mechanism Newest model (2026); long-term/whole-organism phenotype (skin, neurodevelopmental features) not addressed by this HSPC-focused system
Patient fibroblasts/keratinocytes Direct human-cell confirmation of loss of function and NLRP1 activation Ex vivo; does not model whole-organism disease course

This table itself illustrates a textbook HUMAN_MODEL_MISMATCH knowledge-gap pattern (per this repository's curation conventions): standard mouse knockout/knock-in models systematically failed to explain the defining human hematologic phenotype for several years (2013 tongue-muscle paper through the 2022 Science Immunology paper) until species-specific CARD8 biology was directly tested in a humanized reverse-genetics system in 2026 — a prompt, explicit, and well-documented case of a mechanism resolved specifically because a model-organism limitation (mouse CARD8 absence) was identified and worked around, rather than silently extrapolated across species.

Key Primary Sources (PMID-cited)

  1. Harapas CR, Robinson KS, Lay K, et al. DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling. Sci Immunol. 2022 Sep 16;7(75):eabi4611. PMID:36112693 — disease-defining founding paper (3 families, 4 patients; DPP9 variant characterization; mouse and zebrafish genetic rescue).
  2. Wolf C, Fischer H, Kühl JS, et al. Hemophagocytic lymphohistiocytosis–like hyperinflammation due to a de novo mutation in DPP9. J Allergy Clin Immunol. 2023 Nov;152(5):1336–1344.e5. PMID:37544411 — distinct dominant-negative monoallelic DPP9 disorder; important nosological contrast.
  3. Xiao T, Brewer JR, Carlino M, et al. Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency. J Clin Invest. 2026;136(18). DOI:10.1172/JCI207530. PMID:42427515 — mechanistic resolution of the human-specific CARD8/HSPC pyroptosis pathway; most recent and most directly mechanistic source.
  4. Singh S, Garg A, Mandal P. Recurrent Transfusions and Severe Infections: Unmasking Hatipoglu Immunodeficiency Syndrome: Case Report and Review of Literature. J Pediatr Hematol Oncol. PMID:41082409 — 2025 twin case report expanding the clinical/ancestral spectrum; DHR-test differential-diagnosis pitfall.
  5. Structural/mechanistic background (NLRP1-FIIND-DPP9 ternary complex): "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation," Nature 2021 — cite and verify exact PMID directly from Nature/PubMed at curation time before use as an evidence snippet, since this session identified the paper by title/journal via search but did not independently confirm its PMID through a direct abstract fetch.
  6. OMIM #620331 (HATIS phenotype) and OMIM 608258 (DPP9 gene) — structured database entries for identifiers, clinical synopsis, and molecular genetics summary (content in this report was obtained via MedGen/search-engine mirrors of the OMIM clinical synopsis, since a direct OMIM.org fetch returned HTTP 403 in this session; re-verify directly against OMIM at curation time*, as this report's OMIM-sourced content is a secondary reconstruction, not a direct-fetch primary read).

Explicit Gaps and Caveats for Curation

  • No Orphanet, GeneReviews, or ICD-10/11 entry exists — confirmed by direct search, not merely unfound.
  • Quantitative treatment-outcome and dosing details (e.g., the anakinra 2–4 mg/kg/day figure) were obtained via AI-generated search-engine summaries rather than a direct primary-source fetch in this session and must be re-verified against full-text primary literature before being entered as a cited/quoted evidence item.
  • gnomAD allele frequencies for the specific reported DPP9 variants were not independently verified in this session and should be looked up directly (per this repository's "never write an identifier/statistic from memory" discipline) before populating a ClinVar/gnomAD-sourced field.
  • No validated quality-of-life data exist for this disease.
  • No population-level prevalence/incidence estimate exists (fewer than 10 published patients); any curated Prevalence record should reflect CASES_IN_LITERATURE/NOT_YET_DOCUMENTED, not an invented number.
  • The exact PMID for the 2021 Nature DPP9–NLRP1 ternary-complex structural paper was not independently confirmed via direct PubMed fetch in this session (only via secondary search-result titles) and should be confirmed before citation.
  • The neurodevelopmental/skeletal phenotype's mechanistic link to inflammasome dysregulation is unestablished — flagged above as a candidate knowledge gap rather than asserted as inflammasome-driven.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 5
Off topic 0

All extracted references resolved successfully.