Ichthyosis

disease

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Also known as disorder of cornificationDOCfish scale diseasefish skin diseaseichthyosis (disease)

Summary

Ichthyosis (MONDO:0019269) is a disease caused by variants in KRT1 and KRT10, with 18 cohort genes and 24 clinical trials. The dominant Reactome pathway is Formation of the cornified envelope (6 cohort genes). Top therapeutic interventions include cravacitinib, isotretinoin, and ustekinumab.

At a glance

Causal genes: KRT1 (GenCC Strong), KRT10 (GenCC Strong)
Cohort genes: 18
ClinVar variants: 20
Clinical trials: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ichthyosis
Mondo ID	MONDO:0019269
MeSH	D007057
Orphanet	79354
DOID	DOID:1697
NCIT	C84776
UMLS	C0020757
MedGen	7002
GARD	0018985
MedDRA	10021198
Is cancer (heuristic)	no

Also known as: disorder of cornification · DOC · fish scale disease · fish skin disease · ichthyosis · ichthyosis (disease)

Data availability: 20 ClinVar variants · 4 GenCC gene-disease records · 1 HPO phenotype · 15 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis

Subtypes (3): inherited ichthyosis, acquired ichthyosis, ichthyosis, follicular

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

20 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 likely pathogenic, 5 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39546	NM_001139.3(ALOX12B):c.1562A>G (p.Tyr521Cys)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
217301	NM_021628.3(ALOXE3):c.418C>T (p.Arg140Ter)	ALOXE3	Pathogenic	criteria provided, single submitter
617845	NC_000017.11:g.8113975_8119273delinsC	ALOXE3	Pathogenic	no assertion criteria provided
523448	NM_002016.2(FLG):c.544A>T (p.Lys182Ter)	CCDST	Pathogenic	criteria provided, single submitter
545515	NM_000878.5(IL2RB):c.286C>T (p.Gln96Ter)	IL2RB	Pathogenic	no assertion criteria provided
617846	NM_001374623.1(PNPLA1):c.387C>A (p.Asp129Glu)	PNPLA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374374	GRCh37/hg19 Xp22.31(chrX:6497085-7910475)	PNPLA4	Pathogenic	no assertion criteria provided
813270	Single allele	PNPLA4	Pathogenic	no assertion criteria provided
3384054	NM_173076.3(ABCA12):c.2785C>T (p.Arg929Cys)	ABCA12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384055	NM_173076.3(ABCA12):c.2486dup (p.Arg830fs)	ABCA12	Likely pathogenic	criteria provided, single submitter
3384056	NM_173076.3(ABCA12):c.335del (p.Ser112fs)	ABCA12	Likely pathogenic	criteria provided, single submitter
55838	NM_001378789.1(CERS3):c.609+1G>T	CERS3	Likely pathogenic	criteria provided, single submitter
126419	NM_021978.4(ST14):c.2269+1G>A	ST14	Likely pathogenic	criteria provided, single submitter
217304	NM_000359.3(TGM1):c.1363T>C (p.Trp455Arg)	TGM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
374101	NM_001139.3(ALOX12B):c.1859C>A (p.Pro620Gln)	ALOX12B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373954	NM_000094.4(COL7A1):c.1442G>A (p.Arg481His)	COL7A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
523566	NM_173483.4(CYP4F22):c.1211T>C (p.Leu404Pro)	CYP4F22	Uncertain significance	criteria provided, single submitter
523567	NM_173483.4(CYP4F22):c.1544G>T (p.Arg515Leu)	CYP4F22	Uncertain significance	criteria provided, single submitter
523447	NM_002016.2(FLG):c.10012A>T (p.Ser3338Cys)	FLG	Uncertain significance	criteria provided, single submitter
2672143	NM_006121.4(KRT1):c.655G>T (p.Asp219Tyr)	KRT1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 60 · 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
KRT1	Definitive	Autosomal dominant	annular epidermolytic ichthyosis	18
KRT10	Definitive	Autosomal dominant	annular epidermolytic ichthyosis	15
PRSS8	Moderate	Autosomal recessive	ichthyosis
UGCG	Limited	Autosomal recessive	ichthyosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT1	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT1	Orphanet:281139	Annular epidermolytic ichthyosis
KRT1	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT1	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT1	Orphanet:50942	Striate palmoplantar keratoderma
KRT1	Orphanet:530838	KRT1-related diffuse nonepidermolytic keratoderma
KRT1	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
KRT1	Orphanet:79503	Ichthyosis hystrix of Curth-Macklin
KRT10	Orphanet:281139	Annular epidermolytic ichthyosis
KRT10	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT10	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT10	Orphanet:512103	Autosomal recessive epidermolytic ichthyosis
ST14	Orphanet:91132	Ichthyosis-hypotrichosis syndrome
TGM1	Orphanet:100976	Bathing suit ichthyosis
TGM1	Orphanet:281122	Self-improving collodion baby
TGM1	Orphanet:281127	Acral self-healing collodion baby
TGM1	Orphanet:313	Lamellar ichthyosis
TGM1	Orphanet:79394	Congenital ichthyosiform erythroderma
ALOXE3	Orphanet:281122	Self-improving collodion baby
ALOXE3	Orphanet:313	Lamellar ichthyosis
ALOXE3	Orphanet:79394	Congenital ichthyosiform erythroderma
ABCA12	Orphanet:313	Lamellar ichthyosis
ABCA12	Orphanet:457	Harlequin ichthyosis
ABCA12	Orphanet:79394	Congenital ichthyosiform erythroderma
PNPLA1	Orphanet:79394	Congenital ichthyosiform erythroderma
COL7A1	Orphanet:158673	Localized dystrophic epidermolysis bullosa, acral form
COL7A1	Orphanet:158676	Localized dystrophic epidermolysis bullosa, nails only
COL7A1	Orphanet:231568	Autosomal dominant generalized dystrophic epidermolysis bullosa
COL7A1	Orphanet:79408	Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
COL7A1	Orphanet:79409	Recessive dystrophic epidermolysis bullosa inversa
COL7A1	Orphanet:79410	Localized dystrophic epidermolysis bullosa, pretibial form
COL7A1	Orphanet:79411	Self-improving dystrophic epidermolysis bullosa
COL7A1	Orphanet:89842	Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form
COL7A1	Orphanet:89843	Dystrophic epidermolysis bullosa pruriginosa
CERS3	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
CERS3	Orphanet:79394	Congenital ichthyosiform erythroderma
CYP4F22	Orphanet:313	Lamellar ichthyosis
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism

Cohort genes → proteins

18 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT1	HGNC:6412	ENSG00000167768	P04264	Keratin, type II cytoskeletal 1	gencc,clinvar
UGCG	HGNC:12524	ENSG00000148154	Q16739	Ceramide glucosyltransferase	gencc
KRT10	HGNC:6413	ENSG00000186395	P13645	Keratin, type I cytoskeletal 10	gencc
PRSS8	HGNC:9491	ENSG00000052344	Q16651	Prostasin	gencc
ST14	HGNC:11344	ENSG00000149418	Q9Y5Y6	Suppressor of tumorigenicity 14 protein	clinvar
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	clinvar
ALOXE3	HGNC:13743	ENSG00000179148	Q9BYJ1	Hydroperoxide isomerase ALOXE3	clinvar
ABCA12	HGNC:14637	ENSG00000144452	Q86UK0	Glucosylceramide transporter ABCA12	clinvar
PNPLA1	HGNC:21246	ENSG00000180316	Q8N8W4	Omega-hydroxyceramide transacylase	clinvar
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar
CERS3	HGNC:23752	ENSG00000154227	Q8IU89	Ceramide synthase 3	clinvar
PNPLA4	HGNC:24887	ENSG00000006757	P41247	Patatin-like phospholipase domain-containing protein 4	clinvar
CYP4F22	HGNC:26820	ENSG00000171954	Q6NT55	Ultra-long-chain fatty acid omega-hydroxylase	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
FLG	HGNC:3748	ENSG00000143631	P20930	Filaggrin	clinvar
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar
IL2RB	HGNC:6009	ENSG00000100385	P14784	Interleukin-2 receptor subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT1	Keratin, type II cytoskeletal 1	May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1).
UGCG	Ceramide glucosyltransferase	Participates in the initial step of the glucosylceramide-based glycosphingolipid/GSL synthetic pathway at the cytosolic surface of the Golgi.
KRT10	Keratin, type I cytoskeletal 10	Plays a role in the establishment of the epidermal barrier on plantar skin.
PRSS8	Prostasin	Possesses a trypsin-like cleavage specificity with a preference for poly-basic substrates.
ST14	Suppressor of tumorigenicity 14 protein	Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site.
TGM1	Protein-glutamine gamma-glutamyltransferase K	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
ALOXE3	Hydroperoxide isomerase ALOXE3	Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity.
ABCA12	Glucosylceramide transporter ABCA12	Transports lipids such as glucosylceramides from the outer to the inner leaflet of lamellar granules (LGs) membrane, whereby the lipids are finally transported to the keratinocyte periphery via the trans-Golgi network and LGs and released…
PNPLA1	Omega-hydroxyceramide transacylase	Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation.
COL7A1	Collagen alpha-1(VII) chain	Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV c…
CERS3	Ceramide synthase 3	Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22).
PNPLA4	Patatin-like phospholipase domain-containing protein 4	Has abundant triacylglycerol lipase activity.
CYP4F22	Ultra-long-chain fatty acid omega-hydroxylase	A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
FLG	Filaggrin	Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.
ALOX12B	Arachidonate 12-lipoxygenase, 12R-type	Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species.
IL2RB	Interleukin-2 receptor subunit beta	Receptor for interleukin-2.

Protein-family classification

Druggable: 12 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	3	4.9×	0.078
Enzyme (other)	5	3.3×	0.078
Protease	2	4.1×	0.199
Transporter	1	4.3×	0.364
Kinase	1	1.5×	0.678
Other/Unknown	5	0.5×	0.996
Transcription factor	1	0.5×	0.996

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT1	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
UGCG	Enzyme (other)	yes	2.4.1.80	Ceramide_glucosylTrfase, Nucleotide-diphossugar_trans
KRT10	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
PRSS8	Protease	yes	3.4.21.B6	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
ST14	Protease	yes	3.4.21.109	SEA_dom, CUB_dom, Trypsin_dom
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
ALOXE3	Enzyme (other)	yes	4.2.1.152	LipOase, PLAT/LH2_dom, LipOase_mml
ABCA12	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
PNPLA1	Enzyme (other)	yes	2.3.1.296	PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
CERS3	Transcription factor	no	2.3.1.24	HD, TLC-dom, Homeodomain-like_sf
PNPLA4	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
CYP4F22	Enzyme (other)	yes	1.14.14.177	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FLG	Other/Unknown	no		S100/CaBP7/8-like_CS, EF_hand_dom, Filaggrin
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml
CCDST	Other/Unknown	no
IL2RB	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

14 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)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of leg	6
upper leg skin	5
lower esophagus mucosa	5
skin of abdomen	5
zone of skin	3
upper arm skin	3
mammalian vulva	2
skin of hip	2
penis	2
mucosa of transverse colon	2
esophagus mucosa	2
stromal cell of endometrium	2
adrenal tissue	1
bronchial epithelial cell	1
minor salivary gland	1
duodenum	1
nasal cavity epithelium	1
diaphragm	1
hindlimb stylopod muscle	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT1	177	tissue_specific	marker	mammalian vulva, upper leg skin, skin of hip
UGCG	274	ubiquitous	marker	upper leg skin, bronchial epithelial cell, adrenal tissue
KRT10	299	broad	marker	upper leg skin, penis, mammalian vulva
PRSS8	201	broad	marker	mucosa of transverse colon, lower esophagus mucosa, minor salivary gland
ST14	246	broad	marker	mucosa of transverse colon, nasal cavity epithelium, duodenum
TGM1	135	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
ALOXE3	141	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin
ABCA12	95	broad	marker	penis, upper leg skin, upper arm skin
PNPLA1	104	tissue_specific	marker	skin of abdomen, skin of leg, zone of skin
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg
CERS3	160	tissue_specific	marker	lower esophagus mucosa, skin of abdomen, esophagus mucosa
PNPLA4	276	ubiquitous	marker	oocyte, hindlimb stylopod muscle, diaphragm
CYP4F22	103	tissue_specific	marker	lower esophagus mucosa, upper arm skin, skin of leg
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
FLG	162	tissue_specific	yes	upper leg skin, upper arm skin, skin of hip
ALOX12B	168	broad	yes	skin of leg, skin of abdomen, zone of skin
CCDST	111	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, quadriceps femoris
IL2RB	208	broad	marker	granulocyte, decidua, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 29.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR1	5,693
KRT1	2,716
KRT10	2,304
FLG	2,165
IL2RB	2,076
UGCG	1,998
TGM1	1,978
COL7A1	1,767
CYP4F22	1,462
ST14	1,383

Intra-cohort edges

A	B	Sources
ABCA12	ALOX12B	string_interaction
ABCA12	ALOXE3	string_interaction
ABCA12	CERS3	string_interaction
ABCA12	CYP4F22	string_interaction
ABCA12	FLG	string_interaction
ABCA12	PNPLA1	string_interaction
ABCA12	TGM1	string_interaction
ALOX12B	ALOXE3	intact
ALOX12B	CERS3	string_interaction
ALOX12B	CYP4F22	string_interaction
ALOX12B	PNPLA1	string_interaction
ALOX12B	TGM1	string_interaction
ALOXE3	CERS3	string_interaction
ALOXE3	CYP4F22	string_interaction
ALOXE3	PNPLA1	string_interaction
ALOXE3	TGM1	string_interaction
CERS3	CYP4F22	string_interaction
CERS3	PNPLA1	string_interaction
CERS3	UGCG	string_interaction
CYP4F22	PNPLA1	string_interaction
CYP4F22	TGM1	string_interaction
FLG	KRT1	string_interaction
FLG	KRT10	string_interaction
FLG	ST14	string_interaction
FLG	TGM1	string_interaction
KRT1	KRT10	biogrid_interaction, intact, string_interaction
KRT1	TGM1	string_interaction
KRT10	TGM1	string_interaction
PNPLA1	TGM1	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 8 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83
ST14	Q9Y5Y6	25
PRSS8	Q16651	9
IL2RB	P14784	8
KRT10	P13645	6
KRT1	P04264	3
TGM1	P22735	1
ALOXE3	Q9BYJ1	1
FLG	P20930	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA4	P41247	94.38
CYP4F22	Q6NT55	93.59
UGCG	Q16739	93.29
ALOX12B	O75342	92.07
CERS3	Q8IU89	87.52
ABCA12	Q86UK0	68.32
PNPLA1	Q8N8W4	64.54
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 67. Enrichment computed across 18 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	6	32.9×	9e-07	KRT1, ST14, TGM1, FLG, KRT10, PRSS8
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	3	52.2×	8e-04	KRT1, FLG, KRT10
Synthesis of 12-eicosatetraenoic acid derivatives	2	203.9×	9e-04	ALOXE3, ALOX12B
Keratinization	4	13.9×	0.003	KRT1, ST14, TGM1, KRT10
Arachidonate metabolism	2	71.4×	0.005	ALOXE3, ALOX12B
Defective CYP4F22 causes ARCI5	1	713.8×	0.013	CYP4F22
Defective ABCA12 causes ARCI4B	1	713.8×	0.013	ABCA12
Developmental Cell Lineages	2	28.0×	0.019	KRT1, KRT10
Signaling by FGFR1 amplification mutants	1	356.9×	0.021	FGFR1
FGFR1c and Klotho ligand binding and activation	1	178.4×	0.034	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	178.4×	0.034	FGFR1
Fatty acid metabolism	2	16.4×	0.036	ALOXE3, ALOX12B
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	89.2×	0.056	FGFR1
FGFR1b ligand binding and activation	1	79.3×	0.056	FGFR1
Regulation of FXIIa and plasma kallikrein activity	1	71.4×	0.056	KRT1
Signaling by activated point mutants of FGFR1	1	59.5×	0.056	FGFR1
Miscellaneous substrates	1	59.5×	0.056	CYP4F22
Eicosanoids	1	59.5×	0.056	CYP4F22
Interleukin-2 signaling	1	59.5×	0.056	IL2RB
Metabolism of lipids	3	5.9×	0.056	UGCG, ALOXE3, ALOX12B
FGFR1c ligand binding and activation	1	47.6×	0.059	FGFR1
Anchoring fibril formation	1	47.6×	0.059	COL7A1
Interleukin-15 signaling	1	47.6×	0.059	IL2RB
Developmental Biology	4	3.6×	0.059	KRT1, ST14, TGM1, KRT10
Fatty acids	1	44.6×	0.059	CYP4F22
Phospholipase C-mediated cascade: FGFR1	1	42.0×	0.060	FGFR1
ABC transporters in lipid homeostasis	1	37.6×	0.060	ABCA12
Glycosphingolipid biosynthesis	1	37.6×	0.060	UGCG
Fibronectin matrix formation	1	35.7×	0.060	COL7A1
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	35.7×	0.060	CYP4F22

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of skin barrier	6	160.8×	1e-10	KRT1, UGCG, ALOXE3, ABCA12, FLG, ALOX12B
cornification	5	309.8×	2e-10	KRT1, TGM1, CERS3, FLG, KRT10
keratinocyte differentiation	6	87.5×	2e-09	ST14, TGM1, UGCG, CERS3, FLG, KRT10
ceramide biosynthetic process	5	123.9×	1e-08	ALOXE3, PNPLA1, CERS3, CYP4F22, ALOX12B
protein lipidation	2	396.5×	3e-04	UGCG, ALOX12B
lipid homeostasis	3	59.5×	4e-04	ABCA12, PNPLA1, PNPLA4
lipid oxidation	2	247.8×	5e-04	ALOXE3, ALOX12B
hepoxilin biosynthetic process	2	247.8×	5e-04	ALOXE3, ALOX12B
lipoxygenase pathway	2	180.2×	8e-04	ALOXE3, ALOX12B
epidermis development	3	37.2×	1e-03	UGCG, COL7A1, CERS3
protein heterotetramerization	2	123.9×	0.002	KRT1, KRT10
sphingolipid metabolic process	2	116.6×	0.002	ALOXE3, ALOX12B
triglyceride catabolic process	2	94.4×	0.002	PNPLA1, PNPLA4
linoleic acid metabolic process	2	82.6×	0.003	ALOXE3, ALOX12B
arachidonate metabolic process	2	56.6×	0.005	ALOXE3, ALOX12B
positive regulation of intracellular lipid transport	1	991.3×	0.009	ABCA12
omega-hydroxyceramide biosynthetic process	1	991.3×	0.009	PNPLA1
corneocyte desquamation	1	495.6×	0.013	ABCA12
vitamin D3 metabolic process	1	495.6×	0.013	FGFR1
positive regulation of mitotic cell cycle DNA replication	1	495.6×	0.013	FGFR1
positive regulation of parathyroid hormone secretion	1	495.6×	0.013	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	495.6×	0.013	FGFR1
intermediate filament organization	2	28.3×	0.014	KRT1, KRT10
glucosylceramide biosynthetic process	1	330.4×	0.014	UGCG
regulation of phosphate transport	1	330.4×	0.014	FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	330.4×	0.014	FGFR1
cell envelope organization	1	330.4×	0.014	TGM1
regulation of lateral mesodermal cell fate specification	1	330.4×	0.014	FGFR1
epithelial cell morphogenesis involved in placental branching	1	330.4×	0.014	ST14
intestinal lipid absorption	1	330.4×	0.014	UGCG

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Imsidolimab, Isotretinoin.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 15

Druggability breadth: 7 of 18 evidence-associated genes (39%) 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
UGCG	MIGLUSTAT
ST14	RIVAROXABAN
FGFR1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
UGCG	5	4
ST14	5	4
KRT1	0	0
KRT10	0	0
PRSS8	0	0
TGM1	0	0
ALOXE3	0	0
ABCA12	0	0
PNPLA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	UGCG
ELIGLUSTAT	4	UGCG
RIVAROXABAN	4	ST14
HEXAMIDINE	4	ST14
PENTAMIDINE	4	ST14
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
ST14	96	Binding:91, ADMET:4, Functional:1
UGCG	44	Binding:41, Functional:3
TGM1	11	Binding:11
PRSS8	2	Binding:2
IL2RB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UGCG	2.4.1.80	ceramide glucosyltransferase
PRSS8	3.4.21.B6
ST14	3.4.21.109	matriptase
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase
ALOXE3	4.2.1.152	hydroperoxy icosatetraenoate dehydratase
PNPLA1	2.3.1.296	omega-hydroxyceramide transacylase
CERS3	2.3.1.24, 2.3.1.298	sphingosine N-acyltransferase, ultra-long-chain ceramide synthase
CYP4F22	1.14.14.177	ultra-long-chain fatty acid omega-hydroxylase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FGFR1	1,465

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
MIGLUSTAT	4	UGCG
ELIGLUSTAT	4	UGCG
RIVAROXABAN	4	ST14
HEXAMIDINE	4	ST14
PENTAMIDINE	4	ST14
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	UGCG, ST14, FGFR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	4	PRSS8, TGM1, ALOXE3, IL2RB
D	Druggable family + AlphaFold only, no drug	5	ABCA12, PNPLA1, COL7A1, CYP4F22, ALOX12B
E	Difficult family or no structure, no drug	6	KRT1, KRT10, CERS3, PNPLA4, FLG, CCDST

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT1	0	—
KRT10	0	—
PRSS8	2	—
TGM1	11	—
ALOXE3	0	—
ABCA12	0	—
PNPLA1	0	—
COL7A1	0	—
CERS3	0	—
PNPLA4	0	—
CYP4F22	0	—
FLG	0	—
ALOX12B	0	—
CCDST	0	—
IL2RB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 24.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	6
PHASE3	2
EARLY_PHASE1	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CRAVACITINIB	4	3
ISOTRETINOIN	4	2
USTEKINUMAB	4	2
DUPILUMAB	4	1
SECUKINUMAB	4	1
IMSIDOLIMAB	3	1
GLYCERYL LAURATE	0	1

Cohort genes: KRT1, UGCG, KRT10, PRSS8, ST14, TGM1, ALOXE3, ABCA12, PNPLA1, COL7A1, CERS3, PNPLA4, CYP4F22, FGFR1, FLG, ALOX12B, CCDST, IL2RB
Drugs: Cravacitinib, Isotretinoin, Ustekinumab, Dupilumab, Secukinumab, Imsidolimab