Periodic fever-infantile enterocolitis-autoinflammatory syndrome

Summary

Periodic fever-infantile enterocolitis-autoinflammatory syndrome (MONDO:0014472) is a disease caused by NLRC4 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NLRC4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 791

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	periodic fever-infantile enterocolitis-autoinflammatory syndrome
Mondo ID	MONDO:0014472
OMIM	616050
Orphanet	436166
UMLS	C4015067
MedGen	863504
GARD	0017725
NORD	1939
Is cancer (heuristic)	no

Also known as: AIFEC · AUTOINFLAMMATION with infantile enterocolitis · Autoinflammation with Infantile Enterocolitis · autoinflammation with infantile enterocolitis · NLRC4-related autoinflammatory syndrome with macrophage activation syndrome · NLRC4-related autoinflammatory syndrome with MAS · NLRC4-related infantile enterocolitis-autoinflammatory syndrome · NLRC4-related macrophage activation syndrome · NLRC4-related MAS

Data availability: 791 ClinVar variants · 3 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 › periodic fever-infantile enterocolitis-autoinflammatory syndrome

Related subtypes (5): TNF receptor 1-associated periodic fever syndrome, autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, 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

600 retrieved; paginated sample, class counts are floors:

354 uncertain significance, 201 likely benign, 23 conflicting classifications of pathogenicity, 11 benign, 4 benign/likely benign, 4 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
143224	NM_001199138.2(NLRC4):c.1022T>C (p.Val341Ala)	NLRC4	Pathogenic	criteria provided, multiple submitters, no conflicts
156462	NM_001199138.2(NLRC4):c.1009A>T (p.Thr337Ser)	NLRC4	Pathogenic	criteria provided, single submitter
161413	NM_001199138.2(NLRC4):c.1328A>C (p.His443Pro)	NLRC4	Pathogenic	criteria provided, single submitter
1804623	NM_001199138.2(NLRC4):c.1333T>C (p.Ser445Pro)	NLRC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429469	NM_001199138.2(NLRC4):c.1021G>T (p.Val341Leu)	NLRC4	Pathogenic	criteria provided, single submitter
2664351	NM_001199138.2(NLRC4):c.390del (p.Ser132fs)	NLRC4	Likely pathogenic	no assertion criteria provided
374310	NM_001199138.2(NLRC4):c.512C>T (p.Ser171Phe)	NLRC4	Likely pathogenic	no assertion criteria provided
1020930	NM_001199138.2(NLRC4):c.26G>A (p.Arg9Gln)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
103085	NM_001199138.2(NLRC4):c.928C>T (p.Arg310Ter)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1052924	NM_001199138.2(NLRC4):c.88del (p.Trp30fs)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1103952	NM_001199138.2(NLRC4):c.822G>C (p.Met274Ile)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1107308	NM_001199138.2(NLRC4):c.1476G>T (p.Arg492=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1109996	NM_001199138.2(NLRC4):c.105C>T (p.Arg35=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1116165	NM_001199138.2(NLRC4):c.249C>T (p.Asp83=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1124109	NM_001199138.2(NLRC4):c.1164G>C (p.Arg388=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1125911	NM_001199138.2(NLRC4):c.298G>A (p.Asp100Asn)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1127367	NM_001199138.2(NLRC4):c.2835G>A (p.Ala945=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1136389	NM_001199138.2(NLRC4):c.2957A>G (p.Lys986Arg)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1158792	NM_001199138.2(NLRC4):c.199A>C (p.Asn67His)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1414057	NM_001199138.2(NLRC4):c.704T>C (p.Met235Thr)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1505585	NM_001199138.2(NLRC4):c.1972G>C (p.Glu658Gln)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1598719	NM_001199138.2(NLRC4):c.1528G>A (p.Ala510Thr)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694362	NM_001199138.2(NLRC4):c.1409_1410dup (p.Asn471fs)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694363	NM_001199138.2(NLRC4):c.1550G>C (p.Cys517Ser)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694384	NM_001199138.2(NLRC4):c.648C>A (p.Leu216=)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1999093	NM_001199138.2(NLRC4):c.2678A>G (p.Gln893Arg)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2323440	NM_001199138.2(NLRC4):c.2714A>G (p.Glu905Gly)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2578849	NM_001199138.2(NLRC4):c.2945C>T (p.Ala982Val)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3756620	NM_001199138.2(NLRC4):c.488G>A (p.Ser163Asn)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475252	NM_001199138.2(NLRC4):c.2357G>T (p.Gly786Val)	NLRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
NLRC4	Strong	Autosomal dominant	periodic fever-infantile enterocolitis-autoinflammatory syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRC4	Orphanet:436166	Periodic fever-infantile enterocolitis-autoinflammatory syndrome
NLRC4	Orphanet:576349	NLRC4-related familial cold autoinflammatory syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NLRC4	HGNC:16412	ENSG00000091106	Q9NPP4	NLR family CARD domain-containing protein 4	gencc,clinvar
SLC30A6	HGNC:19305	ENSG00000152683	Q6NXT4	Zinc transporter 6	clinvar
DPY30	HGNC:24590	ENSG00000162961	Q9C005	Protein dpy-30 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRC4	NLR family CARD domain-containing protein 4	Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis.
SLC30A6	Zinc transporter 6	Has probably no intrinsic transporter activity but together with SLC30A5 forms a functional zinc ion:proton antiporter heterodimer, mediating zinc entry into the lumen of organelles along the secretory pathway.
DPY30	Protein dpy-30 homolog	As part of the MLL1/MLL complex, involved in the methylation of histone H3 at ‘Lys-4’, particularly trimethylation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLRC4	Transcription factor	no		CARD, NACHT_NTPase, DEATH-like_dom_sf
SLC30A6	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, CDF_SLC30A
DPY30	Other/Unknown	no		Dpy-30_motif, Sdc1/DPY30, DPY30_SDC1_DD

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
leukocyte	1
monocyte	1
ileal mucosa	1
left ventricle myocardium	1
tibialis anterior	1
bronchial epithelial cell	1
bronchus	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRC4	166	broad	marker	monocyte, leukocyte, blood
SLC30A6	247	ubiquitous	marker	left ventricle myocardium, tibialis anterior, ileal mucosa
DPY30	256	ubiquitous	marker	bronchial epithelial cell, bronchus, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DPY30	3,894
SLC30A6	1,732
NLRC4	1,564

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DPY30	Q9C005	12
NLRC4	Q9NPP4	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC30A6	Q6NXT4	71.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The IPAF inflammasome	1	2855.0×	0.005	NLRC4
Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome	1	1142.0×	0.006	DPY30
TP53 Regulates Transcription of Caspase Activators and Caspases	1	475.8×	0.009	NLRC4
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.022	DPY30
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.022	DPY30
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.022	DPY30
PKMTs methylate histone lysines	1	80.4×	0.022	DPY30
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.022	DPY30
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.022	DPY30
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	60.1×	0.022	DPY30
Regulation of PD-L1(CD274) transcription	1	54.4×	0.022	DPY30
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.024	DPY30
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.024	DPY30

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of zinc ion transport	1	5617.3×	0.004	SLC30A6
zinc ion import into Golgi lumen	1	1872.4×	0.005	SLC30A6
icosanoid biosynthetic process	1	561.7×	0.008	NLRC4
zinc ion transport	1	510.7×	0.008	SLC30A6
detection of bacterium	1	468.1×	0.008	NLRC4
positive regulation of protein processing	1	401.2×	0.008	NLRC4
pattern recognition receptor signaling pathway	1	330.4×	0.009	NLRC4
pyroptotic inflammatory response	1	170.2×	0.014	NLRC4
activation of innate immune response	1	160.5×	0.014	NLRC4
transcription initiation-coupled chromatin remodeling	1	127.7×	0.016	DPY30
positive regulation of interleukin-1 beta production	1	86.4×	0.020	NLRC4
endosomal transport	1	81.4×	0.020	DPY30
obsolete positive regulation of NF-kappaB transcription factor activity	1	68.5×	0.022	NLRC4
positive regulation of inflammatory response	1	48.4×	0.029	NLRC4
protein homooligomerization	1	40.7×	0.032	NLRC4
defense response to bacterium	1	36.0×	0.034	NLRC4
positive regulation of apoptotic process	1	18.9×	0.061	NLRC4
inflammatory response	1	12.6×	0.086	NLRC4
innate immune response	1	11.2×	0.091	NLRC4
apoptotic process	1	9.6×	0.101	NLRC4

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRC4	0	0
SLC30A6	0	0
DPY30	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NLRC4	13	Binding:13
DPY30	3	Binding:3
SLC30A6	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	NLRC4, SLC30A6, DPY30

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NLRC4	13	—
SLC30A6	1	—
DPY30	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.