Trichohepatoenteric syndrome 2

Summary

Trichohepatoenteric syndrome 2 (MONDO:0013818) is a disease caused by SKIC2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SKIC2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trichohepatoenteric syndrome 2
Mondo ID	MONDO:0013818
OMIM	614602
DOID	DOID:0111416
UMLS	C3281289
MedGen	482919
GARD	0015819
Is cancer (heuristic)	no

Also known as: SKIV2L tricho-hepato-enteric syndrome · THES2 · tricho-hepato-enteric syndrome caused by mutation in SKIV2L · Trichohepatoenteric syndrome 2 · Trichohepatoenteric syndrome type 2

Data availability: 116 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 2

Related subtypes (1): trichohepatoenteric syndrome 1

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

116 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 26 conflicting classifications of pathogenicity, 16 benign, 12 pathogenic, 10 benign/likely benign, 8 pathogenic/likely pathogenic, 5 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
982895	NM_021628.3(ALOXE3):c.680+1G>A	ALOXE3	Pathogenic	criteria provided, multiple submitters, no conflicts
235728	NM_006929.5(SKIC2):c.1120C>T (p.Arg374Ter)	LOC126859653	Pathogenic	criteria provided, multiple submitters, no conflicts
30070	NM_006929.5(SKIC2):c.1022T>G (p.Val341Gly)	LOC126859653	Pathogenic	no assertion criteria provided
1033166	NM_006929.5(SKIC2):c.235C>T (p.Arg79Ter)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301692	NM_006929.5(SKIC2):c.2341-1G>T	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323596	NM_006929.5(SKIC2):c.3187C>T (p.Arg1063Ter)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323597	NM_006929.5(SKIC2):c.1452del (p.Val485fs)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1708562	NM_006929.5(SKIC2):c.1891G>A (p.Gly631Ser)	SKIC2	Pathogenic	no assertion criteria provided
1805097	NM_006929.5(SKIC2):c.510_511insAGCTGAACACACGG (p.Glu171delinsSerTer)	SKIC2	Pathogenic	criteria provided, single submitter
2626980	NM_006929.5(SKIC2):c.2203-1G>A	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2802208	NM_006929.5(SKIC2):c.697C>T (p.Gln233Ter)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30069	NM_006929.5(SKIC2):c.848G>A (p.Trp283Ter)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
30071	NM_006929.5(SKIC2):c.1635_1636insA (p.Gly546fs)	SKIC2	Pathogenic	criteria provided, single submitter
4293314	NM_006929.5(SKIC2):c.779dup (p.Val261fs)	SKIC2	Pathogenic	criteria provided, single submitter
561107	NM_006929.5(SKIC2):c.2341-2A>G	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631978	NM_006929.5(SKIC2):c.757C>T (p.Arg253Ter)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800925	NM_006929.5(SKIC2):c.3561_3581del (p.Ser1189_Leu1195del)	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
869409	NM_006929.5(SKIC2):c.904C>T (p.Gln302Ter)	SKIC2	Pathogenic	criteria provided, single submitter
869410	NM_006929.5(SKIC2):c.2662_2663del (p.Arg888fs)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
929470	NM_006929.5(SKIC2):c.1404-2A>G	SKIC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2119580	NM_006929.5(SKIC2):c.470-1G>A	SKIC2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780604	NM_006929.5(SKIC2):c.2341-1G>C	SKIC2	Likely pathogenic	criteria provided, single submitter
4688028	NM_006929.5(SKIC2):c.2476C>T (p.Gln826Ter)	SKIC2	Likely pathogenic	criteria provided, single submitter
689443	NM_006929.5(SKIC2):c.2977dup (p.Met993fs)	SKIC2	Likely pathogenic	criteria provided, single submitter
929471	NM_006929.5(SKIC2):c.1647+1G>A	SKIC2	Likely pathogenic	criteria provided, single submitter
356322	NM_006929.5(SKIC2):c.954C>T (p.Ala318=)	LOC126859653	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905832	NM_006929.5(SKIC2):c.990C>T (p.Val330=)	LOC126859653	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905833	NM_006929.5(SKIC2):c.1020T>C (p.Val340=)	LOC126859653	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000909	NM_006929.5(SKIC2):c.3252G>A (p.Met1084Ile)	SKIC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064068	NM_006929.5(SKIC2):c.1816C>T (p.Arg606Cys)	SKIC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
SKIC2	Definitive	Autosomal recessive	trichohepatoenteric syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SKIC2	Orphanet:84064	Trichohepatoenteric syndrome
ALOXE3	Orphanet:281122	Self-improving collodion baby
ALOXE3	Orphanet:313	Lamellar ichthyosis
ALOXE3	Orphanet:79394	Congenital ichthyosiform erythroderma

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
SKIC2	HGNC:10898	ENSG00000204351	Q15477	Superkiller complex protein 2	gencc,clinvar
ALOXE3	HGNC:13743	ENSG00000179148	Q9BYJ1	Hydroperoxide isomerase ALOXE3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SKIC2	Superkiller complex protein 2	Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.
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.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SKIC2	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Ski2/MTR4_C
ALOXE3	Enzyme (other)	yes	4.2.1.152	LipOase, PLAT/LH2_dom, LipOase_mml

Expression context

Cohort genes with no expression data: 0.

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
adenohypophysis	1
pituitary gland	1
right lobe of liver	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SKIC2	134	ubiquitous	yes	right lobe of liver, pituitary gland, adenohypophysis
ALOXE3	141	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SKIC2	2,818
ALOXE3	1,129

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SKIC2	Q15477	11
ALOXE3	Q9BYJ1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Synthesis of 12-eicosatetraenoic acid derivatives	1	815.7×	0.010	ALOXE3
Deadenylation-dependent mRNA decay	1	439.2×	0.010	SKIC2
mRNA decay by 3’ to 5’ exoribonuclease	1	356.9×	0.010	SKIC2
Arachidonate metabolism	1	285.5×	0.010	ALOXE3
Chaperonin-mediated protein folding	1	150.3×	0.013	SKIC2
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.013	SKIC2
Protein folding	1	129.8×	0.013	SKIC2
Fatty acid metabolism	1	65.6×	0.023	ALOXE3
Metabolism of RNA	1	20.8×	0.063	SKIC2
Metabolism of lipids	1	15.8×	0.075	ALOXE3
Metabolism of proteins	1	6.2×	0.165	SKIC2
Metabolism	1	5.8×	0.165	ALOXE3

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	SKIC2
nuclear-transcribed mRNA catabolic process, non-stop decay	1	2106.5×	0.003	SKIC2
lipid oxidation	1	1053.2×	0.003	ALOXE3
hepoxilin biosynthetic process	1	1053.2×	0.003	ALOXE3
lipoxygenase pathway	1	766.0×	0.003	ALOXE3
peroxisome proliferator activated receptor signaling pathway	1	766.0×	0.003	ALOXE3
sphingolipid metabolic process	1	495.6×	0.004	ALOXE3
linoleic acid metabolic process	1	351.1×	0.005	ALOXE3
arachidonate metabolic process	1	240.7×	0.006	ALOXE3
rescue of stalled cytosolic ribosome	1	240.7×	0.006	SKIC2
establishment of skin barrier	1	227.7×	0.006	ALOXE3
ceramide biosynthetic process	1	210.7×	0.006	ALOXE3
sensory perception of pain	1	187.2×	0.006	ALOXE3
fat cell differentiation	1	90.6×	0.011	ALOXE3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SKIC2	0	0
ALOXE3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALOXE3	4.2.1.152	hydroperoxy icosatetraenoate dehydratase

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	ALOXE3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SKIC2

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)
SKIC2	0	—
ALOXE3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.