Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive

Summary

Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (MONDO:0014912) is a disease caused by OTULIN (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include propolis wax.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: OTULIN (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive
Mondo ID	MONDO:0014912
OMIM	617099
Orphanet	500062
DOID	DOID:0080163
SNOMED CT	765435009
UMLS	C4310614
MedGen	934581
GARD	0013198
Is cancer (heuristic)	no

Also known as: AIPDS · ORAS · otulin deficiency · otulin-related autoinflammatory syndrome · otulipenia

Data availability: 17 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › periodic fever syndrome › hereditary periodic fever syndrome › autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive

Related subtypes (5): TNF receptor 1-associated periodic fever syndrome, periodic fever-infantile enterocolitis-autoinflammatory syndrome, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, familial Mediterranean fever

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

6 pathogenic, 5 uncertain significance, 2 benign/likely benign, 2 pathogenic; risk factor, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027708	NM_138348.6(OTULIN):c.22C>T (p.Gln8Ter)	OTULIN	Pathogenic	criteria provided, single submitter
1706581	NM_138348.6(OTULIN):c.864+2T>C	OTULIN	Pathogenic	no assertion criteria provided
1706582	NM_138348.6(OTULIN):c.841G>A (p.Gly281Arg)	OTULIN	Pathogenic	no assertion criteria provided
1706583	NM_138348.6(OTULIN):c.258G>A (p.Met86Ile)	OTULIN	Pathogenic	no assertion criteria provided
1706584	NM_138348.6(OTULIN):c.500G>C (p.Trp167Ser)	OTULIN	Pathogenic	no assertion criteria provided
254124	NM_138348.6(OTULIN):c.815T>C (p.Leu272Pro)	OTULIN	Pathogenic	no assertion criteria provided
254125	NM_138348.6(OTULIN):c.517del (p.Gly174fs)	OTULIN	Pathogenic; risk factor	no assertion criteria provided
254126	NM_138348.6(OTULIN):c.731A>G (p.Tyr244Cys)	OTULIN	Pathogenic; risk factor	no assertion criteria provided
4071519	NM_138348.6(OTULIN):c.468+1G>C	OTULIN	Likely pathogenic	criteria provided, single submitter
1602085	NM_138348.6(OTULIN):c.469-10G>C	OTULIN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027709	NM_138348.6(OTULIN):c.553G>T (p.Val185Phe)	OTULIN	Uncertain significance	criteria provided, single submitter
1378534	NM_138348.6(OTULIN):c.17T>C (p.Met6Thr)	OTULIN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1493560	NM_138348.6(OTULIN):c.1052G>A (p.Ser351Asn)	OTULIN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584879	NM_138348.6(OTULIN):c.349T>C (p.Phe117Leu)	OTULIN	Uncertain significance	criteria provided, single submitter
4079483	NM_138348.6(OTULIN):c.315T>A (p.Cys105Ter)	OTULIN	Uncertain significance	criteria provided, single submitter
1168721	NM_138348.6(OTULIN):c.230-15T>A	OTULIN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
717847	NM_138348.6(OTULIN):c.996C>G (p.Leu332=)	OTULIN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
OTULIN	Definitive	Autosomal recessive	autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OTULIN	Orphanet:500062	Infantile-onset periodic fever-panniculitis-dermatosis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OTULIN	HGNC:25118	ENSG00000154124	Q96BN8	Ubiquitin thioesterase otulin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OTULIN	Ubiquitin thioesterase otulin	Deubiquitinase that specifically removes linear (‘Met-1’-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OTULIN	Other/Unknown	no		FAM105, Otulin

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
buccal mucosa cell	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OTULIN	234	ubiquitous	marker	buccal mucosa cell, bone marrow cell, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OTULIN	1,553

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OTULIN	Q96BN8	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.004	OTULIN
Regulation of TNFR1 signaling	1	223.9×	0.004	OTULIN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein linear deubiquitination	1	5617.3×	0.002	OTULIN
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	1532.0×	0.004	OTULIN
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.005	OTULIN
regulation of canonical Wnt signaling pathway	1	543.6×	0.005	OTULIN
sprouting angiogenesis	1	481.5×	0.005	OTULIN
obsolete negative regulation of NF-kappaB transcription factor activity	1	358.6×	0.005	OTULIN
negative regulation of inflammatory response	1	137.0×	0.011	OTULIN
Wnt signaling pathway	1	99.7×	0.014	OTULIN
protein ubiquitination	1	41.4×	0.030	OTULIN
proteolysis	1	34.2×	0.030	OTULIN
innate immune response	1	33.6×	0.030	OTULIN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OTULIN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	OTULIN

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
OTULIN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05413096	EARLY_PHASE1	COMPLETED	Combination of Diclofenac Potassium and Propolis in the Therapy of Oral Aphthosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPOLIS WAX	3	1