Trimethylaminuria

Summary

Trimethylaminuria (MONDO:0011182) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 2
• ClinVar variants: 117
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trimethylaminuria
Mondo ID	MONDO:0011182
Orphanet	35056
ICD-10-CM	E72.52
ICD-11	685690588
SNOMED CT	237959005
UMLS	C0342739
MedGen	83350
GARD	0027797
Is cancer (heuristic)	no

Also known as: fish malodor syndrome · fish odor syndrome · fish odour syndrome · fish-odor syndrome · stale fish syndrome · TMAU · TMAuria · trimethylaminuria · trimethylaminuria (disease)

Data availability: 117 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Subtypes (2): severe primary trimethylaminuria, 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

ClinVar germline variants

117 retrieved; paginated sample, class counts are floors:

32 likely pathogenic, 22 uncertain significance, 20 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 10 pathogenic, 7 benign, 7 benign/likely benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16318	NM_006894.4(FMO3):c.[472G>A;923A>G]		Pathogenic/Likely pathogenic	no assertion criteria provided
217371	NM_006894.4(FMO3):c.[472G>A;560T>C]		Pathogenic	no assertion criteria provided
1322927	NM_001002294.3(FMO3):c.622G>T (p.Glu208Ter)	FMO3	Pathogenic	criteria provided, multiple submitters, no conflicts
16304	NM_001002294.3(FMO3):c.913G>T (p.Glu305Ter)	FMO3	Pathogenic	criteria provided, multiple submitters, no conflicts
16308	NM_001002294.3(FMO3):c.458C>T (p.Pro153Leu)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16309	NM_001002294.3(FMO3):c.1474C>T (p.Arg492Trp)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16312	NM_001002294.3(FMO3):c.940G>T (p.Glu314Ter)	FMO3	Pathogenic	no assertion criteria provided
16315	NG_012690.2:g.4664_16889del	FMO3	Pathogenic	no assertion criteria provided
16317	NM_001002294.3(FMO3):c.192del (p.Glu65fs)	FMO3	Pathogenic	no assertion criteria provided
2627164	NM_001002294.3(FMO3):c.1408C>T (p.Gln470Ter)	FMO3	Pathogenic	criteria provided, single submitter
2717713	NM_001002294.3(FMO3):c.1118dup (p.Ser374fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2719491	NM_001002294.3(FMO3):c.712C>T (p.Arg238Ter)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2720934	NM_001002294.3(FMO3):c.993_994del (p.Tyr331_Ser332delinsTer)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734034	NM_001002294.3(FMO3):c.1498C>T (p.Arg500Ter)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2822929	NM_001002294.3(FMO3):c.559del (p.Val187fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2828328	NM_001002294.3(FMO3):c.237del (p.Asn80fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2833474	NM_001002294.3(FMO3):c.726_729del (p.Phe242fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2914874	NM_001002294.3(FMO3):c.391del (p.Arg131fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2961405	NM_001002294.3(FMO3):c.1139_1140del (p.Pro380fs)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3573961	NM_001002294.3(FMO3):c.458_459del (p.Pro153fs)	FMO3	Pathogenic	criteria provided, single submitter
3573979	NM_001002294.3(FMO3):c.591_594delinsAA (p.Cys197_Asp198delinsTer)	FMO3	Pathogenic	criteria provided, single submitter
379574	NM_001002294.3(FMO3):c.859G>T (p.Glu287Ter)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
562008	NM_001002294.3(FMO3):c.370C>T (p.Gln124Ter)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631576	NM_001002294.3(FMO3):c.929C>T (p.Ser310Leu)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
874042	NM_001002294.3(FMO3):c.713G>A (p.Arg238Gln)	FMO3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225364	NM_001002294.3(FMO3):c.591_592del (p.Cys197_Asp198delinsTer)	LOC126805916	Pathogenic	criteria provided, multiple submitters, no conflicts
1321151	NM_001002294.3(FMO3):c.667C>T (p.Arg223Trp)	FMO3	Likely pathogenic	criteria provided, single submitter
16306	NM_001002294.3(FMO3):c.198G>T (p.Met66Ile)	FMO3	Likely pathogenic	criteria provided, single submitter
16313	NM_001002294.3(FMO3):c.182A>G (p.Asn61Ser)	FMO3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
16314	NM_001002294.3(FMO3):c.1302G>A (p.Met434Ile)	FMO3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

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

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
FMO3	HGNC:3771	ENSG00000007933	P31513	Flavin-containing monooxygenase 3	clinvar
FMO4	HGNC:3772	ENSG00000076258	P31512	Dimethylaniline monooxygenase [N-oxide-forming] 4	clinvar

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.
FMO4	Dimethylaniline monooxygenase [N-oxide-forming] 4	This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides.

Protein-family classification

Druggable: 2 · 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)	2	12.0×	0.007

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
FMO4	Enzyme (other)	yes	1.14.13.8	Flavin_mOase, Flavin_mOase_4, 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
nasal cavity mucosa	1
olfactory segment of nasal mucosa	1
ileal mucosa	1
nephron tubule	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
FMO4	202	tissue_specific	yes	nephron tubule, right lobe of liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FMO3	1,830
FMO4	1,691

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FMO3	P31513	95.50
FMO4	P31512	91.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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 2 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	2106.5×	0.002	FMO3
negative regulation of fatty acid oxidation	1	842.6×	0.003	FMO4
xenobiotic catabolic process	1	280.9×	0.006	FMO4
energy homeostasis	1	135.9×	0.009	FMO4
xenobiotic metabolic process	1	74.6×	0.013	FMO4

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
FMO3	0	0
FMO4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FMO3	10	ADMET:10
FMO4	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FMO3	1.14.13.148, 1.14.13.8	trimethylamine monooxygenase, flavin-containing monooxygenase
FMO4	1.14.13.8	flavin-containing monooxygenase

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	0
D	Druggable family + AlphaFold only, no drug	2	FMO3, FMO4
E	Difficult family or no structure, no drug	0

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)
FMO3	10	—
FMO4	1	—

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