Trichohepatoenteric syndrome 1

Summary

Trichohepatoenteric syndrome 1 (MONDO:0024541) is a disease caused by SKIC3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SKIC3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 74

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trichohepatoenteric syndrome 1
Mondo ID	MONDO:0024541
OMIM	222470
DOID	DOID:0111415
UMLS	C4551982
MedGen	1644087
GARD	0025422
Is cancer (heuristic)	no

Also known as: THES1 · tricho-hepato-enteric syndrome caused by mutation in TTC37 · TRICHOHEPATOENTERIC syndrome 1 · trichohepatoenteric syndrome 1 · TTC37 tricho-hepato-enteric syndrome

Data availability: 74 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › trichohepatoenteric syndrome › trichohepatoenteric syndrome 1

Related subtypes (1): trichohepatoenteric syndrome 2

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

74 retrieved; paginated sample, class counts are floors:

15 conflicting classifications of pathogenicity, 15 pathogenic, 13 uncertain significance, 13 likely pathogenic, 10 pathogenic/likely pathogenic, 4 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
209130	NM_018238.4(AGK):c.409C>T (p.Arg137Ter)	AGK	Pathogenic	criteria provided, multiple submitters, no conflicts
1325251	NM_014639.4(SKIC3):c.828del (p.Ile276fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455116	NM_014639.4(SKIC3):c.1374C>G (p.Tyr458Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675180	NM_014639.4(SKIC3):c.4108C>T (p.Gln1370Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686282	NM_014639.4(SKIC3):c.2849_2850del (p.Glu950fs)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1687274	NM_014639.4(SKIC3):c.231G>A (p.Trp77Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687390	NM_014639.4(SKIC3):c.2842G>T (p.Glu948Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708563	NM_014639.4(SKIC3):c.4102C>T (p.Gln1368Ter)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1896207	NM_014639.4(SKIC3):c.2921-1G>A	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
196135	NM_014639.4(SKIC3):c.2808G>A (p.Trp936Ter)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
2571907	NM_014639.4(SKIC3):c.53_54del (p.Arg18fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3001610	NM_014639.4(SKIC3):c.831del (p.Gly277_Leu278insTer)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
3001972	NM_014639.4(SKIC3):c.3622C>T (p.Gln1208Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065551	NM_014639.4(SKIC3):c.2181_2182del (p.Tyr728fs)	SKIC3	Pathogenic	criteria provided, single submitter
31231	SKIC3, IVS28AS, G-A, -2	SKIC3	Pathogenic	no assertion criteria provided
31232	NM_014639.4(SKIC3):c.1632+1del	SKIC3	Pathogenic	no assertion criteria provided
31233	NM_014639.4(SKIC3):c.439C>T (p.Gln147Ter)	SKIC3	Pathogenic	no assertion criteria provided
31234	NM_014639.4(SKIC3):c.2251C>T (p.Gln751Ter)	SKIC3	Pathogenic	no assertion criteria provided
31237	NM_014639.4(SKIC3):c.4620+1G>C	SKIC3	Pathogenic	no assertion criteria provided
3236455	NM_014639.4(SKIC3):c.2387del (p.Thr796fs)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382202	NM_014639.4(SKIC3):c.154G>T (p.Glu52Ter)	SKIC3	Pathogenic	criteria provided, single submitter
561159	NM_014639.4(SKIC3):c.409C>T (p.Arg137Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
816870	NM_014639.4(SKIC3):c.2662C>T (p.Gln888Ter)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
817666	NM_014639.4(SKIC3):c.3426dup (p.Ala1143fs)	SKIC3	Pathogenic	criteria provided, multiple submitters, no conflicts
827751	NM_014639.4(SKIC3):c.3625C>T (p.Arg1209Ter)	SKIC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332713	NM_014639.4(SKIC3):c.2018G>A (p.Gly673Asp)	SKIC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675179	NM_014639.4(SKIC3):c.2115-1G>A	SKIC3	Likely pathogenic	criteria provided, single submitter
2434307	NM_014639.4(SKIC3):c.2778+2T>G	SKIC3	Likely pathogenic	criteria provided, single submitter
2664221	NM_014639.4(SKIC3):c.3301C>T (p.Gln1101Ter)	SKIC3	Likely pathogenic	criteria provided, single submitter
31235	NM_014639.4(SKIC3):c.2515+1G>C	SKIC3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
SKIC3	Definitive	Autosomal recessive	trichohepatoenteric syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SKIC3	Orphanet:84064	Trichohepatoenteric syndrome
AGK	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
AGK	Orphanet:98994	Total early-onset cataract

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SKIC3	HGNC:23639	ENSG00000198677	Q6PGP7	Superkiller complex protein 3	gencc,clinvar
AGK	HGNC:21869	ENSG00000006530	Q53H12	Acylglycerol kinase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SKIC3	Superkiller complex protein 3	Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.
AGK	Acylglycerol kinase, mitochondrial	Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SKIC3	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, Ski3/TTC37
AGK	Kinase	yes	2.7.1.94	Diacylglycerol_kinase_cat_dom, NAD/diacylglycerol_kinase_sf, ATP-NAD_kinase_N

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
calcaneal tendon	1
stromal cell of endometrium	1
cerebellar cortex	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SKIC3	294	ubiquitous	marker	calcaneal tendon, adrenal tissue, stromal cell of endometrium
AGK	161	ubiquitous	marker	adrenal tissue, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGK	2,341
SKIC3	1,829

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SKIC3	Q6PGP7	7
AGK	Q53H12	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Deadenylation-dependent mRNA decay	1	439.2×	0.015	SKIC3
mRNA decay by 3’ to 5’ exoribonuclease	1	356.9×	0.015	SKIC3
Glycerophospholipid biosynthesis	1	167.9×	0.021	AGK
Oncogenic MAPK signaling	1	124.1×	0.021	AGK
Phospholipid metabolism	1	100.2×	0.021	AGK
Signaling by BRAF and RAF1 fusions	1	85.2×	0.021	AGK
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.055	AGK
Metabolism of RNA	1	20.8×	0.065	SKIC3
Metabolism of lipids	1	15.8×	0.076	AGK
Disease	1	6.5×	0.162	AGK
Metabolism	1	5.8×	0.165	AGK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay	1	2808.7×	0.003	SKIC3
glycerolipid metabolic process	1	1053.2×	0.003	AGK
lipid phosphorylation	1	842.6×	0.003	AGK
protein insertion into mitochondrial inner membrane	1	648.1×	0.003	AGK
sphingosine biosynthetic process	1	526.6×	0.003	AGK
nuclear-transcribed mRNA catabolic process	1	383.0×	0.003	SKIC3
rescue of stalled cytosolic ribosome	1	240.7×	0.005	SKIC3
ceramide biosynthetic process	1	210.7×	0.005	AGK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
SKIC3	0	0
AGK	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
AGK	19	Binding:19
SKIC3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGK	2.7.1.94	acylglycerol kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	AGK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SKIC3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SKIC3	1	—
AGK	19	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.