Severe primary trimethylaminuria

Summary

Severe primary trimethylaminuria (MONDO:0018767) is a disease caused by FMO3 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: FMO3 (GenCC Strong)
• Cohort genes: 1
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0410020	Fish odor	Obligate (100%)
HP:0003614	Trimethylaminuria	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0031467	Negative affectivity	Frequent (30-79%)
HP:0031469	Low self esteem	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0008770	Obsessive-compulsive trait	Occasional (5-29%)
HP:0011999	Paranoia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe primary trimethylaminuria
Mondo ID	MONDO:0018767
MeSH	C536561
OMIM	602079
Orphanet	468726
DOID	DOID:0080361
UMLS	C5575503
MedGen	1814174
GARD	0006447
Is cancer (heuristic)	no

Also known as: fish malodor syndrome · fish odor syndrome · fish odour syndrome · stale fish syndrome · TMAU · TMAuria · trimethylaminuria

Data availability: 3 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › disorder of peptide and amine metabolism › disorder of methylamine metabolism › dimethylglycine dehydrogenase deficiency › trimethylaminuria › severe primary trimethylaminuria

Related subtypes (1): secondary trimethylaminuria

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
FMO3	Strong	Autosomal recessive	severe primary trimethylaminuria	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FMO3	Orphanet:468726	Severe primary trimethylaminuria

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
FMO3	HGNC:3771	ENSG00000007933	P31513	Flavin-containing monooxygenase 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FMO3	Flavin-containing monooxygenase 3	Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds.

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)
FMO3	Enzyme (other)	yes	1.14.13.148	Flavin_mOase, Flavin_mOase_3, Flavin_mOase-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
nasal cavity mucosa	1
olfactory segment of nasal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FMO3	196	tissue_specific	marker	right lobe of liver, olfactory segment of nasal mucosa, nasal cavity mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FMO3	1,830

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FMO3	P31513	95.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Defective FMO3 causes TMAU	1	11420.0×	2e-04	FMO3
FMO oxidises nucleophiles	1	3806.7×	3e-04	FMO3

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
taurine biosynthetic process	1	4213.0×	2e-04	FMO3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
FMO3	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
FMO3	10	ADMET:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FMO3	1.14.13.148, 1.14.13.8	trimethylamine monooxygenase, flavin-containing monooxygenase

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

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	0
D	Druggable family + AlphaFold only, no drug	1	FMO3
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FMO3	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford