Congenital non-bullous ichthyosiform erythroderma

Summary

Congenital non-bullous ichthyosiform erythroderma (MONDO:0019306) is a disease (an umbrella term covering 6 Mondo subtypes) caused by variants in ALOX12B and ALOXE3, with 8 cohort genes and 1 clinical trial. Top therapeutic interventions include secukinumab.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: ALOX12B (GenCC Strong), ALOXE3 (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 3
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.3	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.5	Spain	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000656	Ectropion	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0001019	Erythroderma	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000491	Keratitis	Frequent (30-79%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0200020	Corneal erosion	Frequent (30-79%)
HP:0004322	Short stature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital non-bullous ichthyosiform erythroderma
Mondo ID	MONDO:0019306
Orphanet	79394
DOID	DOID:1699
ICD-11	546439698
SNOMED CT	205550003
UMLS	C0079154
MedGen	38180
GARD	0009736
Is cancer (heuristic)	no

Also known as: alligator skin · CIE · congenital ichthyosiform erythroderma · congenital ichthyosiform erythroderma (disease) · congenital non bullous ichthyosiform erythroderma · erythrodermic ichthyosis · ichthyosiform erythroderma · non-bullous congenital ichthyosiform erythroderma · nonbullous congenital ichthyosiform erythroderma

Data availability: 3 ClinVar variants · 9 GenCC gene-disease records · 1 HPO phenotype · 1 cell line.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › congenital non-bullous ichthyosiform erythroderma

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (6): autosomal recessive congenital ichthyosis 2, autosomal recessive congenital ichthyosis 3, autosomal recessive congenital ichthyosis 6, autosomal recessive congenital ichthyosis 7, autosomal recessive congenital ichthyosis 9, autosomal recessive congenital ichthyosis 10

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

3 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39545	NM_001139.3(ALOX12B):c.1642C>T (p.Arg548Trp)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449286	NM_021628.3(ALOXE3):c.1630C>T (p.Gln544Ter)	ALOXE3	Pathogenic	criteria provided, multiple submitters, no conflicts
1251995	NM_003358.3(UGCG):c.142dup (p.Ser48fs)	UGCG	Conflicting classifications of pathogenicity	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 51 · Orphanet: 19 · 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
ABCA12	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 4B	8
ALOX12B	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 2	8
ALOXE3	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 3	8
NIPAL4	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 6	7
TGM1	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 1	10
CERS3	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 9	4
PNPLA1	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 10	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALOXE3	Orphanet:281122	Self-improving collodion baby
ALOXE3	Orphanet:313	Lamellar ichthyosis
ALOXE3	Orphanet:79394	Congenital ichthyosiform erythroderma
ALOX12B	Orphanet:281122	Self-improving collodion baby
ALOX12B	Orphanet:313	Lamellar ichthyosis
ALOX12B	Orphanet:79394	Congenital ichthyosiform erythroderma
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
ABCA12	Orphanet:313	Lamellar ichthyosis
ABCA12	Orphanet:457	Harlequin ichthyosis
ABCA12	Orphanet:79394	Congenital ichthyosiform erythroderma
PNPLA1	Orphanet:79394	Congenital ichthyosiform erythroderma
CERS3	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
CERS3	Orphanet:79394	Congenital ichthyosiform erythroderma
NIPAL4	Orphanet:313	Lamellar ichthyosis
NIPAL4	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALOXE3	HGNC:13743	ENSG00000179148	Q9BYJ1	Hydroperoxide isomerase ALOXE3	gencc,clinvar
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	gencc,clinvar
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	gencc
ABCA12	HGNC:14637	ENSG00000144452	Q86UK0	Glucosylceramide transporter ABCA12	gencc
PNPLA1	HGNC:21246	ENSG00000180316	Q8N8W4	Omega-hydroxyceramide transacylase	gencc
CERS3	HGNC:23752	ENSG00000154227	Q8IU89	Ceramide synthase 3	gencc
NIPAL4	HGNC:28018	ENSG00000172548	Q0D2K0	Magnesium transporter NIPA4	gencc
UGCG	HGNC:12524	ENSG00000148154	Q16739	Ceramide glucosyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
TGM1	Protein-glutamine gamma-glutamyltransferase K	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
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.
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).
NIPAL4	Magnesium transporter NIPA4	Acts as a Mg(2+) transporter.
UGCG	Ceramide glucosyltransferase	Participates in the initial step of the glucosylceramide-based glycosphingolipid/GSL synthetic pathway at the cytosolic surface of the Golgi.

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.75

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
Enzyme (other)	4	6.0×	0.013
Transporter	1	9.7×	0.246
Antibody/Immunoglobulin	1	3.6×	0.406
Transcription factor	1	1.0×	0.805
Other/Unknown	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALOXE3	Enzyme (other)	yes	4.2.1.152	LipOase, PLAT/LH2_dom, LipOase_mml
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
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
CERS3	Transcription factor	no	2.3.1.24	HD, TLC-dom, Homeodomain-like_sf
NIPAL4	Other/Unknown	no		Mg_trans_NIPA, EmrE-like
UGCG	Enzyme (other)	yes	2.4.1.80	Ceramide_glucosylTrfase, Nucleotide-diphossugar_trans

Expression context

Cohort genes with no expression data: 0.

6 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	5
skin of leg	5
zone of skin	3
esophagus mucosa	2
lower esophagus mucosa	2
upper arm skin	2
upper leg skin	2
penis	1
adrenal tissue	1
bronchial epithelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALOXE3	141	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin
ALOX12B	168	broad	yes	skin of leg, skin of abdomen, zone of skin
TGM1	135	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
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
CERS3	160	tissue_specific	marker	lower esophagus mucosa, skin of abdomen, esophagus mucosa
NIPAL4	165	broad	marker	upper arm skin, skin of abdomen, skin of leg
UGCG	274	ubiquitous	marker	upper leg skin, bronchial epithelial cell, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UGCG	1,998
TGM1	1,978
ABCA12	1,137
ALOXE3	1,129
ALOX12B	1,126
CERS3	837
PNPLA1	584
NIPAL4	540

Intra-cohort edges

A	B	Sources
ABCA12	ALOX12B	string_interaction
ABCA12	ALOXE3	string_interaction
ABCA12	CERS3	string_interaction
ABCA12	NIPAL4	string_interaction
ABCA12	PNPLA1	string_interaction
ABCA12	TGM1	string_interaction
ALOX12B	ALOXE3	intact
ALOX12B	CERS3	string_interaction
ALOX12B	NIPAL4	string_interaction
ALOX12B	PNPLA1	string_interaction
ALOX12B	TGM1	string_interaction
ALOXE3	CERS3	string_interaction
ALOXE3	NIPAL4	string_interaction
ALOXE3	PNPLA1	string_interaction
ALOXE3	TGM1	string_interaction
CERS3	NIPAL4	string_interaction
CERS3	PNPLA1	string_interaction
CERS3	UGCG	string_interaction
NIPAL4	PNPLA1	string_interaction
NIPAL4	TGM1	string_interaction
PNPLA1	TGM1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALOXE3	Q9BYJ1	1
TGM1	P22735	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
UGCG	Q16739	93.29
ALOX12B	O75342	92.07
CERS3	Q8IU89	87.52
NIPAL4	Q0D2K0	78.91
ABCA12	Q86UK0	68.32
PNPLA1	Q8N8W4	64.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of 12-eicosatetraenoic acid derivatives	2	466.1×	1e-04	ALOXE3, ALOX12B
Arachidonate metabolism	2	163.1×	6e-04	ALOXE3, ALOX12B
Defective ABCA12 causes ARCI4B	1	1631.4×	0.004	ABCA12
Fatty acid metabolism	2	37.5×	0.005	ALOXE3, ALOX12B
Metabolism of lipids	3	13.5×	0.005	ALOXE3, ALOX12B, UGCG
ABC transporters in lipid homeostasis	1	85.9×	0.033	ABCA12
Glycosphingolipid biosynthesis	1	85.9×	0.033	UGCG
Miscellaneous transport and binding events	1	62.8×	0.034	NIPAL4
ABC transporter disorders	1	62.8×	0.034	ABCA12
Metabolism	3	5.0×	0.034	ALOXE3, ALOX12B, UGCG
Glycosphingolipid metabolism	1	42.9×	0.040	UGCG
Sphingolipid de novo biosynthesis	1	40.8×	0.040	CERS3
Sphingolipid metabolism	1	24.0×	0.063	UGCG
Disorders of transmembrane transporters	1	19.9×	0.070	ABCA12
ABC-family protein mediated transport	1	17.4×	0.075	ABCA12
Formation of the cornified envelope	1	12.6×	0.096	TGM1
Keratinization	1	8.0×	0.140	TGM1
Transport of small molecules	1	3.6×	0.275	ABCA12
Developmental Biology	1	2.1×	0.415	TGM1
Disease	1	1.9×	0.427	ABCA12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 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	4	227.7×	5e-08	ALOXE3, ALOX12B, UGCG, ABCA12
ceramide biosynthetic process	4	210.7×	5e-08	ALOXE3, ALOX12B, PNPLA1, CERS3
protein lipidation	2	842.6×	4e-05	ALOX12B, UGCG
keratinocyte differentiation	3	92.9×	5e-05	TGM1, UGCG, CERS3
lipid oxidation	2	526.6×	5e-05	ALOXE3, ALOX12B
hepoxilin biosynthetic process	2	526.6×	5e-05	ALOXE3, ALOX12B
lipoxygenase pathway	2	383.0×	8e-05	ALOXE3, ALOX12B
cornification	2	263.3×	2e-04	TGM1, CERS3
sphingolipid metabolic process	2	247.8×	2e-04	ALOXE3, ALOX12B
linoleic acid metabolic process	2	175.5×	3e-04	ALOXE3, ALOX12B
arachidonate metabolic process	2	120.4×	6e-04	ALOXE3, ALOX12B
lipid homeostasis	2	84.3×	0.001	ABCA12, PNPLA1
positive regulation of intracellular lipid transport	1	2106.5×	0.002	ABCA12
omega-hydroxyceramide biosynthetic process	1	2106.5×	0.002	PNPLA1
epidermis development	2	52.7×	0.002	UGCG, CERS3
corneocyte desquamation	1	1053.2×	0.003	ABCA12
glucosylceramide biosynthetic process	1	702.2×	0.004	UGCG
cell envelope organization	1	702.2×	0.004	TGM1
intestinal lipid absorption	1	702.2×	0.004	UGCG
positive regulation of mucus secretion	1	421.3×	0.006	ALOX12B
cornified envelope assembly	1	351.1×	0.007	UGCG
leptin-mediated signaling pathway	1	300.9×	0.008	UGCG
secretion by cell	1	210.7×	0.011	ABCA12
peroxisome proliferator activated receptor signaling pathway	1	191.5×	0.011	ALOXE3
ceramide transport	1	191.5×	0.011	ABCA12
magnesium ion transport	1	150.5×	0.013	NIPAL4
regulation of keratinocyte differentiation	1	150.5×	0.013	ABCA12
phospholipid efflux	1	140.4×	0.014	ABCA12
positive regulation of keratinocyte proliferation	1	123.9×	0.015	TGM1
regulation of insulin secretion involved in cellular response to glucose stimulus	1	117.0×	0.015	ABCA12

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 2 of 8 evidence-associated genes (25%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UGCG	5	4
ALOXE3	0	0
ALOX12B	0	0
TGM1	0	0
ABCA12	0	0
PNPLA1	0	0
CERS3	0	0
NIPAL4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	UGCG
ELIGLUSTAT	4	UGCG
LUCERASTAT	3	UGCG
VENGLUSTAT	3	UGCG
NIZUBAGLUSTAT	2	UGCG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
UGCG	44	Binding:41, Functional:3
TGM1	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALOXE3	4.2.1.152	hydroperoxy icosatetraenoate dehydratase
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase
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
UGCG	2.4.1.80	ceramide glucosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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
LUCERASTAT	3	UGCG
VENGLUSTAT	3	UGCG
NIZUBAGLUSTAT	2	UGCG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	UGCG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ALOXE3, TGM1
D	Druggable family + AlphaFold only, no drug	3	ALOX12B, ABCA12, PNPLA1
E	Difficult family or no structure, no drug	2	CERS3, NIPAL4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALOXE3	0	—
ALOX12B	0	—
TGM1	11	—
ABCA12	0	—
PNPLA1	0	—
CERS3	0	—
NIPAL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SECUKINUMAB	4	1