Lamellar ichthyosis

disease

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Also known as classic lamellar ichthyosiscongenital lamellar ichthyosisLI

Summary

Lamellar ichthyosis (MONDO:0017778) is a disease (an umbrella term covering 6 Mondo subtypes) with 12 cohort genes and 4 clinical trials. Top therapeutic interventions include secukinumab.

At a glance

Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
Umbrella term: 6 Mondo subtypes
Cohort genes: 12
ClinVar variants: 132
Phenotypes (HPO): 21
Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.35	Spain	Validated
Point prevalence	1-9 / 100 000	1.1	Norway	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000656	Ectropion	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0001019	Erythroderma	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0100679	Lack of skin elasticity	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0011039	Abnormality of the helix	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000389	Chronic otitis media	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0100758	Gangrene	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lamellar ichthyosis
Mondo ID	MONDO:0017778
Orphanet	313
ICD-10-CM	Q80.2
ICD-11	600146417
NCIT	C84805
UMLS	C5848247
MedGen	1852191
GARD	0010803
MedDRA	10023686
NORD	1289
Is cancer (heuristic)	no

Also known as: classic lamellar ichthyosis · congenital lamellar ichthyosis · LI

Data availability: 132 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lamellar ichthyosis

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (6): ichthyosis, lamellar, autosomal dominant, autosomal recessive congenital ichthyosis 4A, autosomal recessive congenital ichthyosis 5, autosomal recessive congenital ichthyosis 3, autosomal recessive congenital ichthyosis 6, autosomal recessive congenital ichthyosis 8

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

132 retrieved; paginated sample, class counts are floors:

45 pathogenic, 41 pathogenic/likely pathogenic, 39 likely pathogenic, 7 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1385145	NM_173076.3(ABCA12):c.1210C>T (p.Arg404Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
1455934	NM_173076.3(ABCA12):c.2956C>T (p.Arg986Trp)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526238	NM_173076.3(ABCA12):c.4540C>T (p.Arg1514Cys)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
264998	NM_173076.3(ABCA12):c.179G>C (p.Arg60Pro)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265000	NM_173076.3(ABCA12):c.1300C>T (p.Arg434Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
2734378	NM_173076.3(ABCA12):c.3470C>T (p.Ser1157Leu)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2857	NM_173076.3(ABCA12):c.4541G>A (p.Arg1514His)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2862	NM_173076.3(ABCA12):c.6610C>T (p.Arg2204Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
3366816	NM_173076.3(ABCA12):c.3548A>G (p.Tyr1183Cys)	ABCA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3896372	NM_173076.3(ABCA12):c.5366_5373del (p.Gln1789fs)	ABCA12	Pathogenic	criteria provided, single submitter
3902323	NM_173076.3(ABCA12):c.2125del (p.Met709fs)	ABCA12	Pathogenic	criteria provided, single submitter
419453	NM_173076.3(ABCA12):c.7444C>T (p.Arg2482Ter)	ABCA12	Pathogenic	criteria provided, multiple submitters, no conflicts
1380312	NM_001139.3(ALOX12B):c.1926+1G>A	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265039	NM_001139.3(ALOX12B):c.1790C>A (p.Ala597Glu)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3374962	NM_001139.3(ALOX12B):c.324C>G (p.Tyr108Ter)	ALOX12B	Pathogenic	criteria provided, single submitter
3384712	NM_001139.3(ALOX12B):c.1662dup (p.Arg555Ter)	ALOX12B	Pathogenic	criteria provided, single submitter
3896024	NM_001139.3(ALOX12B):c.1654G>T (p.Gly552Cys)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39545	NM_001139.3(ALOX12B):c.1642C>T (p.Arg548Trp)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39546	NM_001139.3(ALOX12B):c.1562A>G (p.Tyr521Cys)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
632292	NM_001139.3(ALOX12B):c.928-2A>G	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982978	NM_001139.3(ALOX12B):c.1272dup (p.Lys425fs)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
995481	NM_001139.3(ALOX12B):c.71T>C (p.Leu24Pro)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995489	NM_001139.3(ALOX12B):c.1463G>A (p.Arg488His)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
217301	NM_021628.3(ALOXE3):c.418C>T (p.Arg140Ter)	ALOXE3	Pathogenic	criteria provided, single submitter
279677	NM_021628.3(ALOXE3):c.1889C>T (p.Pro630Leu)	ALOXE3	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
4847442	NM_021628.3(ALOXE3):c.1078dup (p.Ala360fs)	ALOXE3	Pathogenic	criteria provided, single submitter
633813	NM_021628.3(ALOXE3):c.2065C>T (p.Arg689Trp)	ALOXE3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982895	NM_021628.3(ALOXE3):c.680+1G>A	ALOXE3	Pathogenic	criteria provided, multiple submitters, no conflicts
2429320	NM_001378789.1(CERS3):c.686G>A (p.Arg229His)	CERS3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 59 · Orphanet: 26 · 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
CYP4F22	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 5	3
LIPN	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 8	4
SDR9C7	Strong	Autosomal recessive	ichthyosis, congenital, autosomal recessive 13	5
SULT2B1	Strong	Autosomal recessive	ichthyosis, congenital, autosomal recessive 14	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CYP4F22	Orphanet:313	Lamellar ichthyosis
NIPAL4	Orphanet:313	Lamellar ichthyosis
NIPAL4	Orphanet:79394	Congenital ichthyosiform erythroderma
SDR9C7	Orphanet:313	Lamellar ichthyosis
SDR9C7	Orphanet:79394	Congenital ichthyosiform erythroderma
ALOX12B	Orphanet:281122	Self-improving collodion baby
ALOX12B	Orphanet:313	Lamellar ichthyosis
ALOX12B	Orphanet:79394	Congenital ichthyosiform erythroderma
SULT2B1	Orphanet:313	Lamellar ichthyosis
SULT2B1	Orphanet:79394	Congenital ichthyosiform erythroderma
LIPN	Orphanet:313	Lamellar ichthyosis
SLC27A4	Orphanet:88621	Ichthyosis-prematurity syndrome
PNPLA1	Orphanet:79394	Congenital ichthyosiform erythroderma
CERS3	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
CERS3	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	gencc,clinvar
ALOXE3	HGNC:13743	ENSG00000179148	Q9BYJ1	Hydroperoxide isomerase ALOXE3	gencc,clinvar
ABCA12	HGNC:14637	ENSG00000144452	Q86UK0	Glucosylceramide transporter ABCA12	gencc,clinvar
CYP4F22	HGNC:26820	ENSG00000171954	Q6NT55	Ultra-long-chain fatty acid omega-hydroxylase	gencc,clinvar
NIPAL4	HGNC:28018	ENSG00000172548	Q0D2K0	Magnesium transporter NIPA4	gencc,clinvar
SDR9C7	HGNC:29958	ENSG00000170426	Q8NEX9	Short-chain dehydrogenase/reductase family 9C member 7	gencc,clinvar
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	gencc,clinvar
SULT2B1	HGNC:11459	ENSG00000088002	O00204	Sulfotransferase 2B1	gencc
LIPN	HGNC:23452	ENSG00000204020	Q5VXI9	Lipase member N	gencc
SLC27A4	HGNC:10998	ENSG00000167114	Q6P1M0	Long-chain fatty acid transport protein 4	clinvar
PNPLA1	HGNC:21246	ENSG00000180316	Q8N8W4	Omega-hydroxyceramide transacylase	clinvar
CERS3	HGNC:23752	ENSG00000154227	Q8IU89	Ceramide synthase 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
CYP4F22	Ultra-long-chain fatty acid omega-hydroxylase	A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis.
NIPAL4	Magnesium transporter NIPA4	Acts as a Mg(2+) transporter.
SDR9C7	Short-chain dehydrogenase/reductase family 9C member 7	Plays a crucial role in the formation of the epidermal permeability barrier.
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.
SULT2B1	Sulfotransferase 2B1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation.
LIPN	Lipase member N	Plays a highly specific role in the last step of keratinocyte differentiation.
SLC27A4	Long-chain fatty acid transport protein 4	Mediates the levels of long-chain fatty acids (LCFA) in the cell by facilitating their transport across cell membranes.
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).

Protein-family classification

Druggable: 7 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.58

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)	5	5.0×	0.010
Transporter	1	6.5×	0.360
Antibody/Immunoglobulin	1	2.4×	0.570
Transcription factor	1	0.7×	0.969
Other/Unknown	4	0.6×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
CYP4F22	Enzyme (other)	yes	1.14.14.177	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
NIPAL4	Other/Unknown	no		Mg_trans_NIPA, EmrE-like
SDR9C7	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml
SULT2B1	Other/Unknown	no		Sulfotransferase_dom, P-loop_NTPase
LIPN	Other/Unknown	no		AB_hydrolase_1, Lipase_euk, AB_hydrolase_fold
SLC27A4	Enzyme (other)	yes	6.2.1.3	AMP-dep_synth/lig_dom, AMP-binding_CS, Lipocalin_CS
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

Expression context

Cohort genes with no expression data: 0.

7 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	8
skin of leg	7
lower esophagus mucosa	5
zone of skin	4
esophagus mucosa	3
upper arm skin	3
penis	1
upper leg skin	1
leukocyte	1
monocyte	1
jejunal mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
CYP4F22	103	tissue_specific	marker	lower esophagus mucosa, upper arm skin, skin of leg
NIPAL4	165	broad	marker	upper arm skin, skin of abdomen, skin of leg
SDR9C7	113	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
SULT2B1	198	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of abdomen
LIPN	88	tissue_specific	yes	monocyte, leukocyte, skin of abdomen
SLC27A4	219	ubiquitous	yes	mucosa of transverse colon, lower esophagus mucosa, jejunal mucosa
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

Protein interactions among cohort

Intra-cohort edges: 54.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC27A4	2,199
TGM1	1,978
CYP4F22	1,462
LIPN	1,288
ABCA12	1,137
ALOXE3	1,129
ALOX12B	1,126
SULT2B1	953
CERS3	837
SDR9C7	785

Intra-cohort edges

A	B	Sources
ABCA12	ALOX12B	string_interaction
ABCA12	ALOXE3	string_interaction
ABCA12	CERS3	string_interaction
ABCA12	CYP4F22	string_interaction
ABCA12	LIPN	string_interaction
ABCA12	NIPAL4	string_interaction
ABCA12	PNPLA1	string_interaction
ABCA12	SDR9C7	string_interaction
ABCA12	TGM1	string_interaction
ALOX12B	ALOXE3	intact
ALOX12B	CERS3	string_interaction
ALOX12B	CYP4F22	string_interaction
ALOX12B	LIPN	string_interaction
ALOX12B	NIPAL4	string_interaction
ALOX12B	PNPLA1	string_interaction
ALOX12B	SDR9C7	string_interaction
ALOX12B	SLC27A4	string_interaction
ALOX12B	SULT2B1	string_interaction
ALOX12B	TGM1	string_interaction
ALOXE3	CERS3	string_interaction
ALOXE3	CYP4F22	string_interaction
ALOXE3	LIPN	string_interaction
ALOXE3	NIPAL4	string_interaction
ALOXE3	PNPLA1	string_interaction
ALOXE3	SDR9C7	string_interaction
ALOXE3	SLC27A4	string_interaction
ALOXE3	SULT2B1	string_interaction
ALOXE3	TGM1	string_interaction
CERS3	CYP4F22	string_interaction
CERS3	LIPN	string_interaction
CERS3	NIPAL4	string_interaction
CERS3	PNPLA1	string_interaction
CERS3	SDR9C7	string_interaction
CERS3	SULT2B1	biogrid_interaction, string_interaction
CYP4F22	LIPN	string_interaction
CYP4F22	NIPAL4	string_interaction
CYP4F22	PNPLA1	string_interaction
CYP4F22	SDR9C7	string_interaction
CYP4F22	SLC27A4	string_interaction
CYP4F22	SULT2B1	string_interaction
CYP4F22	TGM1	string_interaction
LIPN	NIPAL4	string_interaction
LIPN	PNPLA1	string_interaction
LIPN	TGM1	string_interaction
NIPAL4	PNPLA1	string_interaction
NIPAL4	SDR9C7	string_interaction
NIPAL4	SLC27A4	intact, string_interaction
NIPAL4	SULT2B1	string_interaction
NIPAL4	TGM1	string_interaction
PNPLA1	SDR9C7	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SULT2B1	O00204	4
TGM1	P22735	1
ALOXE3	Q9BYJ1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP4F22	Q6NT55	93.59
SDR9C7	Q8NEX9	93.41
LIPN	Q5VXI9	92.14
ALOX12B	O75342	92.07
SLC27A4	Q6P1M0	90.72
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: 29. Enrichment computed across 12 evidence-associated genes (11 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 11 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	296.6×	5e-04	ALOXE3, ALOX12B
Arachidonate metabolism	2	103.8×	0.002	ALOXE3, ALOX12B
Defective CYP4F22 causes ARCI5	1	1038.2×	0.006	CYP4F22
Defective SLC27A4 causes ichthyosis prematurity syndrome (IPS)	1	1038.2×	0.006	SLC27A4
Defective ABCA12 causes ARCI4B	1	1038.2×	0.006	ABCA12
Disorders of transmembrane transporters	2	25.3×	0.013	ABCA12, SLC27A4
Fatty acid metabolism	2	23.9×	0.013	ALOXE3, ALOX12B
Formation of the cornified envelope	2	16.0×	0.024	TGM1, LIPN
Transport of fatty acids	1	129.8×	0.025	SLC27A4
Miscellaneous substrates	1	86.5×	0.030	CYP4F22
Eicosanoids	1	86.5×	0.030	CYP4F22
Fatty acids	1	64.9×	0.035	CYP4F22
Keratinization	2	10.1×	0.035	TGM1, LIPN
ABC transporters in lipid homeostasis	1	54.6×	0.036	ABCA12
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	51.9×	0.036	CYP4F22
Cytosolic sulfonation of small molecules	1	47.2×	0.036	SULT2B1
The canonical retinoid cycle in rods (twilight vision)	1	47.2×	0.036	SDR9C7
Miscellaneous transport and binding events	1	39.9×	0.038	NIPAL4
ABC transporter disorders	1	39.9×	0.038	ABCA12
Sphingolipid de novo biosynthesis	1	25.9×	0.055	CERS3
Transport of vitamins, nucleosides, and related molecules	1	24.7×	0.055	SLC27A4
Metabolism of lipids	2	5.7×	0.060	ALOXE3, ALOX12B
SLC transporter disorders	1	18.5×	0.066	SLC27A4
Transport of small molecules	2	4.6×	0.083	ABCA12, SLC27A4
ABC-family protein mediated transport	1	11.0×	0.101	ABCA12
SLC-mediated transmembrane transport	1	5.4×	0.187	SLC27A4
Developmental Biology	2	2.6×	0.187	TGM1, LIPN
Disease	2	2.4×	0.211	ABCA12, SLC27A4
Metabolism	2	2.1×	0.244	ALOXE3, ALOX12B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ceramide biosynthetic process	5	175.5×	3e-09	ALOXE3, CYP4F22, ALOX12B, PNPLA1, CERS3
cornification	3	263.3×	5e-06	TGM1, LIPN, CERS3
establishment of skin barrier	3	113.9×	5e-05	ALOXE3, ABCA12, ALOX12B
lipid oxidation	2	351.1×	2e-04	ALOXE3, ALOX12B
hepoxilin biosynthetic process	2	351.1×	2e-04	ALOXE3, ALOX12B
lipoxygenase pathway	2	255.3×	3e-04	ALOXE3, ALOX12B
sphingolipid metabolic process	2	165.2×	6e-04	ALOXE3, ALOX12B
linoleic acid metabolic process	2	117.0×	0.001	ALOXE3, ALOX12B
arachidonate metabolic process	2	80.2×	0.002	ALOXE3, ALOX12B
steroid metabolic process	2	56.2×	0.004	SDR9C7, SULT2B1
lipid homeostasis	2	56.2×	0.004	ABCA12, PNPLA1
positive regulation of intracellular lipid transport	1	1404.3×	0.004	ABCA12
omega-hydroxyceramide biosynthetic process	1	1404.3×	0.004	PNPLA1
keratinocyte differentiation	2	41.3×	0.005	TGM1, CERS3
medium-chain fatty acid transport	1	702.2×	0.006	SLC27A4
corneocyte desquamation	1	702.2×	0.006	ABCA12
cell envelope organization	1	468.1×	0.009	TGM1
protein lipidation	1	280.9×	0.013	ALOX12B
positive regulation of mucus secretion	1	280.9×	0.013	ALOX12B
lipid transport across blood-brain barrier	1	280.9×	0.013	SLC27A4
glucose import in response to insulin stimulus	1	234.1×	0.014	SLC27A4
very long-chain fatty acid catabolic process	1	200.6×	0.016	SLC27A4
positive regulation of epidermal cell differentiation	1	175.5×	0.018	SULT2B1
icosanoid metabolic process	1	156.0×	0.019	CYP4F22
secretion by cell	1	140.4×	0.019	ABCA12
long-chain fatty acid import into cell	1	140.4×	0.019	SLC27A4
peroxisome proliferator activated receptor signaling pathway	1	127.7×	0.020	ALOXE3
ceramide transport	1	127.7×	0.020	ABCA12
magnesium ion transport	1	100.3×	0.023	NIPAL4
regulation of keratinocyte differentiation	1	100.3×	0.023	ABCA12

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 12

Druggability breadth: 3 of 12 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGM1	0	0
ALOXE3	0	0
ABCA12	0	0
CYP4F22	0	0
NIPAL4	0	0
SDR9C7	0	0
ALOX12B	0	0
SULT2B1	0	0
LIPN	0	0
SLC27A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
TGM1	11	Binding:11
SULT2B1	2	ADMET:2
SLC27A4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase
ALOXE3	4.2.1.152	hydroperoxy icosatetraenoate dehydratase
CYP4F22	1.14.14.177	ultra-long-chain fatty acid omega-hydroxylase
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase
SLC27A4	6.2.1.3	long-chain-fatty-acid-CoA ligase
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

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; 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	2	TGM1, ALOXE3
D	Druggable family + AlphaFold only, no drug	5	ABCA12, CYP4F22, ALOX12B, SLC27A4, PNPLA1
E	Difficult family or no structure, no drug	5	NIPAL4, SDR9C7, SULT2B1, LIPN, CERS3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TGM1	11	—
ALOXE3	0	—
ABCA12	0	—
CYP4F22	0	—
NIPAL4	0	—
SDR9C7	0	—
ALOX12B	0	—
SULT2B1	2	—
LIPN	0	—
SLC27A4	1	—
PNPLA1	0	—
CERS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SECUKINUMAB	4	1

Cohort genes: TGM1, ALOXE3, ABCA12, CYP4F22, NIPAL4, SDR9C7, ALOX12B, SULT2B1, LIPN, SLC27A4, PNPLA1, CERS3
Drugs: Secukinumab