Autosomal recessive congenital ichthyosis 1

Summary

Autosomal recessive congenital ichthyosis 1 (MONDO:0009441) is a disease caused by TGM1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TGM1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 456

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 1
Mondo ID	MONDO:0009441
MeSH	D017490
OMIM	242300
DOID	DOID:0060656
UMLS	C4551630
MedGen	1635401
GARD	0003170
Is cancer (heuristic)	no

Also known as: ARCI1 · autosomal recessive congenital ichthyosis 1 · autosomal recessive congenital ichthyosis type 1 · collodion fetus · collodion foetus · desquamation of newborn · ichthyosis congenita · ichthyosis lamellar 1 · ichthyosis, congenital, autosomal recessive 1 · ichthyosis, congenital, autosomal recessive type 1 · ichthyosis, lamellar, 1 · lamellar exfoliation of newborn · lamellar ichthyosis, type 1 · LI1

Data availability: 456 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › autosomal recessive congenital ichthyosis › autosomal recessive congenital ichthyosis 1

Related subtypes (12): autosomal recessive congenital ichthyosis 4A, autosomal recessive congenital ichthyosis 11, autosomal recessive congenital ichthyosis 5, autosomal recessive congenital ichthyosis 8, ichthyosis, congenital, autosomal recessive 12, bathing suit ichthyosis, self-healing collodion baby, acral self-healing collodion baby, exfoliative ichthyosis, congenital non-bullous ichthyosiform erythroderma, ichthyosis, congenital, autosomal recessive 14, ichthyosis, congenital, autosomal recessive 13

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

456 retrieved; paginated sample, class counts are floors:

130 uncertain significance, 91 likely pathogenic, 63 pathogenic, 58 pathogenic/likely pathogenic, 52 conflicting classifications of pathogenicity, 39 likely benign, 14 benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4076949	NM_000359.3(TGM1):c.[1403-355_2225+1704dup;2225+1706_2225+1707insCCACCATCTGTGACCACCATCTGT]		Pathogenic	criteria provided, single submitter
426107	NM_177973.2(SULT2B1):c.446C>T (p.Pro149Leu)	SULT2B1	Pathogenic	criteria provided, single submitter
1050812	NM_000359.3(TGM1):c.674_675delinsCT (p.Arg225Pro)	TGM1	Pathogenic	criteria provided, single submitter
1068254	NM_000359.3(TGM1):c.1438A>T (p.Ile480Phe)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074310	NM_000359.3(TGM1):c.211C>T (p.Arg71Ter)	TGM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075202	NM_000359.3(TGM1):c.1774C>T (p.Gln592Ter)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1195231	NM_000359.3(TGM1):c.1264A>T (p.Lys422Ter)	TGM1	Pathogenic	criteria provided, multiple submitters, no conflicts
12478	NM_000359.3(TGM1):c.1297del (p.Trp433fs)	TGM1	Pathogenic	no assertion criteria provided
12481	NM_000359.3(TGM1):c.428G>A (p.Arg143His)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12482	NM_000359.3(TGM1):c.479C>G (p.Ser160Cys)	TGM1	Pathogenic	no assertion criteria provided
12483	NM_000359.3(TGM1):c.424C>T (p.Arg142Cys)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12484	NM_000359.3(TGM1):c.968G>A (p.Arg323Gln)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12485	NM_000359.3(TGM1):c.425G>A (p.Arg142His)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12486	NM_000359.3(TGM1):c.1135G>C (p.Val379Leu)	TGM1	Pathogenic	criteria provided, multiple submitters, no conflicts
12487	NM_000359.3(TGM1):c.1187G>T (p.Arg396Leu)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12488	NM_000359.3(TGM1):c.1147G>A (p.Val383Met)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12489	NM_000359.3(TGM1):c.1166G>A (p.Arg389His)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12490	NM_000359.3(TGM1):c.2114del (p.Gln705fs)	TGM1	Pathogenic	no assertion criteria provided
12491	NM_000359.3(TGM1):c.1469A>G (p.Asp490Gly)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12492	NM_000359.3(TGM1):c.832G>A (p.Gly278Arg)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12493	NM_000359.3(TGM1):c.1175G>A (p.Gly392Asp)	TGM1	Pathogenic	no assertion criteria provided
12495	NM_000359.3(TGM1):c.857G>A (p.Arg286Gln)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12498	NM_000359.3(TGM1):c.866A>C (p.Asn289Thr)	TGM1	Pathogenic	no assertion criteria provided
12499	NM_000359.3(TGM1):c.919C>T (p.Arg307Trp)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12500	NM_000359.3(TGM1):c.652G>A (p.Gly218Ser)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333234	NM_000359.3(TGM1):c.984+1G>A	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339202	NM_000359.3(TGM1):c.844C>T (p.Gln282Ter)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391349	NM_000359.3(TGM1):c.1721dup (p.Ser575fs)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1419049	NM_000359.3(TGM1):c.607C>T (p.Gln203Ter)	TGM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1420948	NM_000359.3(TGM1):c.395_398dup (p.Tyr134fs)	TGM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 10 · 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
TGM1	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 1	10

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
SULT2B1	Orphanet:313	Lamellar ichthyosis
SULT2B1	Orphanet:79394	Congenital ichthyosiform erythroderma
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy

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
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	gencc,clinvar
SULT2B1	HGNC:11459	ENSG00000088002	O00204	Sulfotransferase 2B1	clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	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.
SULT2B1	Sulfotransferase 2B1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation.
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
SULT2B1	Other/Unknown	no		Sulfotransferase_dom, P-loop_NTPase
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf

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
esophagus mucosa	2
lower esophagus mucosa	2
skin of leg	1
skin of abdomen	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	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
SULT2B1	198	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of abdomen
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGM1	1,978
TNNT2	1,944
SULT2B1	953

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNT2	P45379	25
SULT2B1	O00204	4
TGM1	P22735	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Cytosolic sulfonation of small molecules	1	173.0×	0.024	SULT2B1
Striated Muscle Contraction	1	102.9×	0.024	TNNT2
Formation of the cornified envelope	1	29.3×	0.056	TGM1
Keratinization	1	18.6×	0.066	TGM1
Developmental Biology	1	4.8×	0.194	TGM1

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
cell envelope organization	1	1872.4×	0.006	TGM1
positive regulation of epidermal cell differentiation	1	702.2×	0.006	SULT2B1
regulation of muscle contraction	1	561.7×	0.006	TNNT2
negative regulation of ATP-dependent activity	1	561.7×	0.006	TNNT2
positive regulation of ATP-dependent activity	1	468.1×	0.006	TNNT2
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	374.5×	0.006	SULT2B1
muscle filament sliding	1	351.1×	0.006	TNNT2
sulfation	1	351.1×	0.006	SULT2B1
cornification	1	351.1×	0.006	TGM1
positive regulation of keratinocyte proliferation	1	330.4×	0.006	TGM1
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.008	TNNT2
regulation of heart contraction	1	165.2×	0.011	TNNT2
positive regulation of cell cycle	1	147.8×	0.011	TGM1
cardiac muscle contraction	1	133.8×	0.011	TNNT2
sarcomere organization	1	127.7×	0.011	TNNT2
steroid metabolic process	1	112.3×	0.012	SULT2B1
response to calcium ion	1	106.0×	0.012	TNNT2
keratinocyte differentiation	1	82.6×	0.014	TGM1
protein modification process	1	81.4×	0.014	TGM1
cholesterol metabolic process	1	65.3×	0.016	SULT2B1
negative regulation of cell population proliferation	1	14.0×	0.070	SULT2B1

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): Trifarotene.

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGM1	0	0
SULT2B1	0	0
TNNT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TGM1	11	Binding:11
SULT2B1	2	ADMET:2
TNNT2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TGM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SULT2B1, TNNT2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TGM1	11	—
SULT2B1	2	—
TNNT2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.