Familial hypertryptophanemia

Summary

Familial hypertryptophanemia (MONDO:0010907) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0003144	Increased serum serotonin	Very frequent (80-99%)
HP:0003361	Tryptophanuria	Very frequent (80-99%)
HP:0500134	Hypertryptophanemia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypertryptophanemia
Mondo ID	MONDO:0010907
MeSH	C538393
OMIM	600627
Orphanet	2224
DOID	DOID:0111703
SNOMED CT	721838005
UMLS	C2931837
MedGen	419177
GARD	0002871
Is cancer (heuristic)	no

Also known as: familial hypertryptophanemia · hypertryptophanemia · HYPTRP

Data availability: 2 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of tryptophan metabolism › familial hypertryptophanemia

Related subtypes (2): encephalopathy due to hydroxykynureninuria, inborn disorder of lysine, hydroxylysine, and tryptophan metabolism

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

2 retrieved; paginated sample, class counts are floors:

2 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
440854	NM_005651.4(TDO2):c.491dup (p.Ile165fs)	TDO2	no classifications from unflagged records	no classifications from unflagged records
440855	NM_005651.4(TDO2):c.324G>C (p.Met108Ile)	TDO2	no classifications from unflagged records	no classifications from unflagged records

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
TDO2	Supportive	Autosomal recessive	familial hypertryptophanemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TDO2	Orphanet:2224	Hypertryptophanemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TDO2	HGNC:11708	ENSG00000151790	P48775	Tryptophan 2,3-dioxygenase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TDO2	Tryptophan 2,3-dioxygenase	Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TDO2	Enzyme (other)	yes	1.13.11.11	Trp_2_3_dOase, Trp/Indoleamine_2_3_dOase-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TDO2	127	broad	marker	right lobe of liver, liver, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TDO2	1,753

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TDO2	P48775	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tryptophan catabolism	1	761.3×	0.004	TDO2
Metabolism of amino acids and derivatives	1	67.6×	0.022	TDO2
Metabolism	1	11.6×	0.086	TDO2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-tryptophan catabolic process to acetyl-CoA	1	8426.0×	4e-04	TDO2
response to nitroglycerin	1	8426.0×	4e-04	TDO2
obsolete L-tryptophan catabolic process to L-kynurenine	1	2808.7×	7e-04	TDO2
response to cortisol	1	1685.2×	9e-04	TDO2
protein homotetramerization	1	237.3×	0.005	TDO2
response to ethanol	1	146.5×	0.007	TDO2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
TDO2	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TDO2	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TDO2
EPACADOSTAT	3	TDO2
NAVOXIMOD	2	TDO2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TDO2	152	Binding:152

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TDO2	1.13.11.11, 1.13.11.52	tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TDO2	152

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
BERBERINE	4	TDO2
EPACADOSTAT	3	TDO2
NAVOXIMOD	2	TDO2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TDO2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.