IFAP syndrome 1, with or without BRESHECK syndrome

Summary

IFAP syndrome 1, with or without BRESHECK syndrome (MONDO:0100213) is a disease caused by MBTPS2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MBTPS2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 19
• Phenotypes (HPO): 78

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

78 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001595	Abnormality of the hair	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0000499	Abnormal eyelash morphology	Frequent (30-79%)
HP:0000614	Abnormal nasolacrimal system morphology	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0000966	Hypohidrosis	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0001804	Hypoplastic fingernail	Frequent (30-79%)
HP:0001812	Hyperconvex fingernails	Frequent (30-79%)
HP:0002046	Heat intolerance	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002223	Absent eyebrow	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002721	Immunodeficiency	Frequent (30-79%)
HP:0004370	Abnormality of temperature regulation	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012742	Thin fingernail	Frequent (30-79%)
HP:0045074	Thin eyebrow	Frequent (30-79%)
HP:0200020	Corneal erosion	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000072	Hydroureter	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000453	Choanal atresia	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000491	Keratitis	Occasional (5-29%)
HP:0000492	Abnormal eyelid morphology	Occasional (5-29%)
HP:0000498	Blepharitis	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	IFAP syndrome 1, with or without BRESHECK syndrome
Mondo ID	MONDO:0100213
MeSH	C536085
OMIM	308205
Orphanet	2273
DOID	DOID:0111821
UMLS	C5399971
MedGen	1746744
GARD	0015297
Is cancer (heuristic)	no

Also known as: ichthyosis follicularis atrichia photophobia syndrome · ichthyosis follicularis, atrichia, and photophobia with or without brain anomalies, retardation, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, Ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia · ichthyosis follicularis-alopecia-photophobia syndrome · IFAP syndrome with or without BRESHECK syndrome · IFAP syndrome with or without BRESHECK syndrome, X-linked recessive · IFAP/BRESHECK syndrome

Data availability: 19 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked recessive disease › IFAP syndrome 1, with or without BRESHECK syndrome

Related subtypes (11): retinitis pigmentosa 6, hypophosphatemic rickets, X-linked recessive, Brunner syndrome, X-linked lymphoproliferative disease due to XIAP deficiency, blue cone monochromacy, recessive X-linked ichthyosis, X-linked complicated spastic paraplegia type 1, X-linked recessive ocular albinism, X-linked lymphoproliferative disease due to SH2D1A deficiency, holoprosencephaly 13, X-linked, X-linked recessive mitochondrial myopathy

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

19 retrieved; paginated sample, class counts are floors:

11 pathogenic, 7 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
590275	NM_004004.6(GJB2):c.526A>G (p.Asn176Asp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
11402	NM_015884.4(MBTPS2):c.680A>T (p.His227Leu)	MBTPS2	Pathogenic	no assertion criteria provided
11403	NM_015884.4(MBTPS2):c.261G>A (p.Met87Ile)	MBTPS2	Pathogenic	no assertion criteria provided
11404	NM_015884.4(MBTPS2):c.1286G>A (p.Arg429His)	MBTPS2	Pathogenic	criteria provided, multiple submitters, no conflicts
11405	NM_015884.4(MBTPS2):c.1424T>C (p.Phe475Ser)	MBTPS2	Pathogenic	no assertion criteria provided
11406	NM_015884.4(MBTPS2):c.677G>T (p.Trp226Leu)	MBTPS2	Pathogenic	no assertion criteria provided
126904	NM_015884.4(MBTPS2):c.671-9T>G	MBTPS2	Pathogenic	no assertion criteria provided
4528364	NM_015884.4(MBTPS2):c.970+5G>A	MBTPS2	Pathogenic	criteria provided, multiple submitters, no conflicts
932243	NM_004176.5(SREBF1):c.1579C>T (p.Arg527Cys)	SREBF1	Pathogenic	criteria provided, multiple submitters, no conflicts
932244	NM_004176.5(SREBF1):c.1582_1584del (p.Asn528del)	SREBF1	Pathogenic	no assertion criteria provided
932245	NM_004176.5(SREBF1):c.1589T>C (p.Leu530Pro)	SREBF1	Pathogenic	no assertion criteria provided
2441801	NM_015884.4(MBTPS2):c.527G>A (p.Gly176Glu)	MBTPS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029416	NM_015884.4(MBTPS2):c.516A>C (p.Glu172Asp)	MBTPS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582521	NM_015884.4(MBTPS2):c.670+2688G>C	MBTPS2	Uncertain significance	criteria provided, single submitter
3065261	NM_015884.4(MBTPS2):c.971-6_971-5del	MBTPS2	Uncertain significance	criteria provided, single submitter
3598208	NM_015884.4(MBTPS2):c.1418A>T (p.Asn473Ile)	MBTPS2	Uncertain significance	criteria provided, single submitter
522925	NM_015884.4(MBTPS2):c.529A>C (p.Ile177Leu)	MBTPS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
931186	NM_015884.4(MBTPS2):c.119A>C (p.Asn40Thr)	MBTPS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
931207	NM_015884.4(MBTPS2):c.1520C>T (p.Ala507Val)	MBTPS2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 15 · 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
MBTPS2	Definitive	X-linked	IFAP syndrome 1, with or without BRESHECK syndrome	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MBTPS2	Orphanet:216796	Osteogenesis imperfecta type 1
MBTPS2	Orphanet:216812	Osteogenesis imperfecta type 3
MBTPS2	Orphanet:216820	Osteogenesis imperfecta type 4
MBTPS2	Orphanet:2273	Ichthyosis follicularis-alopecia-photophobia syndrome
MBTPS2	Orphanet:2340	Keratosis follicularis spinulosa decalvans
MBTPS2	Orphanet:659	Mutilating palmoplantar keratoderma with periorificial keratotic plaques
MBTPS2	Orphanet:85284	BRESEK syndrome
SREBF1	Orphanet:388	Hirschsprung disease
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
MBTPS2	HGNC:15455	ENSG00000012174	O43462	Membrane-bound transcription factor site-2 protease	gencc,clinvar
SREBF1	HGNC:11289	ENSG00000072310	P36956	Sterol regulatory element-binding protein 1	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MBTPS2	Membrane-bound transcription factor site-2 protease	Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2.
SREBF1	Sterol regulatory element-binding protein 1	Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBTPS2	Protease	yes	3.4.24.85	MBTPS2, Peptidase_M50, PDZ_sf
SREBF1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

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
endothelial cell	1
parietal pleura	1
tibia	1
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland	1
gingiva	1
gingival epithelium	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBTPS2	264	ubiquitous	marker	endothelial cell, tibia, parietal pleura
SREBF1	172	ubiquitous	marker	left adrenal gland, right adrenal gland, left adrenal gland cortex
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SREBF1	4,089
MBTPS2	2,136
GJB2	1,391

Intra-cohort edges

A	B	Sources
MBTPS2	SREBF1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
SREBF1	P36956	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MBTPS2	O43462	87.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of cholesterol biosynthesis by SREBP (SREBF)	2	211.5×	9e-04	MBTPS2, SREBF1
Metabolism of steroids	2	91.7×	0.002	MBTPS2, SREBF1
Oligomerization of connexins into connexons	1	1268.9×	0.006	GJB2
Transport of connexins along the secretory pathway	1	1268.9×	0.006	GJB2
ATF6B (ATF6-beta) activates chaperones	1	951.7×	0.007	MBTPS2
ATF6 (ATF6-alpha) activates chaperones	1	634.4×	0.008	MBTPS2
Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)	1	423.0×	0.008	SREBF1
CREB3 factors activate genes	1	423.0×	0.008	MBTPS2
Cholesterol biosynthesis	1	380.7×	0.008	SREBF1
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	380.7×	0.008	SREBF1
Metabolism of lipids	2	21.0×	0.009	MBTPS2, SREBF1
R-HSA-1368082	1	237.9×	0.011	SREBF1
Assembly of active LPL and LIPC lipase complexes	1	200.3×	0.012	MBTPS2
Transport of connexons to the plasma membrane	1	181.3×	0.013	GJB2
Plasma lipoprotein remodeling	1	158.6×	0.013	MBTPS2
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	135.9×	0.014	SREBF1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.014	SREBF1
Unfolded Protein Response (UPR)	1	119.0×	0.014	MBTPS2
R-HSA-400253	1	115.3×	0.014	SREBF1
FOXO-mediated transcription	1	112.0×	0.014	SREBF1
Gap junction assembly	1	97.6×	0.016	GJB2
Activation of gene expression by SREBF (SREBP)	1	86.5×	0.017	SREBF1
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.018	MBTPS2
Metabolism	2	7.7×	0.028	MBTPS2, SREBF1
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.029	SREBF1
PPARA activates gene expression	1	31.5×	0.039	SREBF1
Cellular responses to stress	1	12.3×	0.094	MBTPS2
Cellular responses to stimuli	1	10.5×	0.106	MBTPS2
Transport of small molecules	1	8.4×	0.126	MBTPS2
RNA Polymerase II Transcription	1	7.5×	0.136	SREBF1

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
positive regulation of cholesterol biosynthetic process	2	749.0×	1e-04	MBTPS2, SREBF1
regulation of heart rate by chemical signal	1	1872.4×	0.007	SREBF1
bone maturation	1	1872.4×	0.007	MBTPS2
negative regulation of triglyceride metabolic process	1	1404.3×	0.007	SREBF1
regulation of response to endoplasmic reticulum stress	1	1123.5×	0.007	MBTPS2
gap junction-mediated intercellular transport	1	936.2×	0.007	GJB2
response to fructose	1	802.5×	0.007	SREBF1
gap junction assembly	1	702.2×	0.007	GJB2
ATF6-mediated unfolded protein response	1	702.2×	0.007	MBTPS2
obsolete regulation of protein targeting to mitochondrion	1	702.2×	0.007	SREBF1
regulation of fatty acid metabolic process	1	624.1×	0.007	SREBF1
SREBP signaling pathway	1	624.1×	0.007	SREBF1
response to glucagon	1	561.7×	0.007	SREBF1
regulation of cholesterol biosynthetic process	1	510.7×	0.007	MBTPS2
positive regulation of triglyceride biosynthetic process	1	432.1×	0.007	SREBF1
membrane protein intracellular domain proteolysis	1	401.2×	0.007	MBTPS2
regulation of mitophagy	1	401.2×	0.007	SREBF1
lipid biosynthetic process	1	330.4×	0.008	SREBF1
cellular response to fatty acid	1	234.1×	0.011	SREBF1
response to cAMP	1	170.2×	0.013	SREBF1
response to food	1	165.2×	0.013	SREBF1
response to progesterone	1	165.2×	0.013	SREBF1
negative regulation of insulin secretion	1	165.2×	0.013	SREBF1
mitotic G2 DNA damage checkpoint signaling	1	147.8×	0.014	MBTPS2
insulin secretion	1	144.0×	0.014	SREBF1
cholesterol biosynthetic process	1	140.4×	0.014	SREBF1
response to retinoic acid	1	127.7×	0.014	SREBF1
mRNA transcription by RNA polymerase II	1	110.1×	0.016	SREBF1
response to nutrient	1	98.5×	0.017	SREBF1
endoplasmic reticulum unfolded protein response	1	98.5×	0.017	MBTPS2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SREBF1	CALCIFEDIOL ANHYDROUS
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SREBF1	1	4
GJB2	1	4
MBTPS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CALCIFEDIOL ANHYDROUS	4	SREBF1
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SREBF1	17	Binding:17
GJB2	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MBTPS2	3.4.24.85	S2P endopeptidase

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

2 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.

Compound	Max phase	Cohort target (bioactivity)
CALCIFEDIOL ANHYDROUS	4	SREBF1
KANAMYCIN	4	GJB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SREBF1, GJB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MBTPS2
E	Difficult family or no structure, no drug	0

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)
MBTPS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.