Maple syrup urine disease type 2

Summary

Maple syrup urine disease type 2 (MONDO:0023693) is a disease caused by DBT (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: DBT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 53

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maple syrup urine disease type 2
Mondo ID	MONDO:0023693
OMIM	620699
DOID	DOID:0061207
UMLS	C1855371
MedGen	343337
GARD	0008596
Is cancer (heuristic)	no

Also known as: maple syrup urine disease type 2 · MSUD type 2 · MSUD2

Data availability: 53 ClinVar variants · 2 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 organic aciduria › maple syrup urine disease › maple syrup urine disease type 2

Related subtypes (8): pyruvate dehydrogenase E3 deficiency, maple syrup urine disease, mild variant, classic maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, maple syrup urine disease type 1A, maple syrup urine disease type 1B

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

53 retrieved; paginated sample, class counts are floors:

20 pathogenic, 13 likely pathogenic, 12 pathogenic/likely pathogenic, 4 uncertain significance, 3 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11942	NM_001918.3:c.48_171del	DBT	Pathogenic	no assertion criteria provided
11943	NM_001918.5(DBT):c.827T>G (p.Phe276Cys)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11944	NM_001918.3(DBT):c.434_435insAATACCTTGTTACCAGA	DBT	Pathogenic	no assertion criteria provided
11945	NM_001918.5(DBT):c.1017+1del	DBT	Pathogenic	no assertion criteria provided
11946	NM_001918.5(DBT):c.1018-550A>G	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11947	NM_001918.5(DBT):c.1448G>T (p.Ter483Leu)	DBT	Pathogenic	no assertion criteria provided
11948	NM_001918.5(DBT):c.294C>G (p.Ile98Met)	DBT	Pathogenic	no assertion criteria provided
11950	NM_001918.5(DBT):c.75_76del (p.Cys26fs)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
11951	NM_001918.3(DBT):c.1282-4142_*(434_435)del	DBT	Pathogenic	no assertion criteria provided
11952	NM_001918.5(DBT):c.1355A>G (p.His452Arg)	DBT	Pathogenic	no assertion criteria provided
11953	NM_001918.5(DBT):c.581C>G (p.Ser194Ter)	DBT	Pathogenic	no assertion criteria provided
1331436	NM_001918.5(DBT):c.363_364del (p.Tyr122fs)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
1342860	NM_001918.5(DBT):c.916T>C (p.Ser306Pro)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
1397613	NM_001918.5(DBT):c.113_114del (p.Cys38fs)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407245	NM_001918.5(DBT):c.1385G>C (p.Arg462Pro)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
2822401	NM_001918.5(DBT):c.280C>T (p.Gln94Ter)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064163	NM_001918.5(DBT):c.30G>A (p.Trp10Ter)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239659	NM_001918.5(DBT):c.881T>G (p.Leu294Ter)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241277	NM_001918.5(DBT):c.713del (p.Pro238fs)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
3574696	NM_001918.5(DBT):c.1281+1G>A	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293857	NM_001918.5(DBT):c.939+2T>C	DBT	Pathogenic	criteria provided, single submitter
550402	NM_001918.5(DBT):c.1017G>A (p.Lys339=)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551600	NM_001918.5(DBT):c.1195T>G (p.Ser399Ala)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554556	NM_001918.5(DBT):c.1126C>T (p.Arg376Cys)	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635310	NM_001918.5(DBT):c.898del (p.Ala300fs)	DBT	Pathogenic	criteria provided, single submitter
93991	NM_001918.5(DBT):c.1291C>T (p.Arg431Ter)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
94002	NM_001918.5(DBT):c.360del (p.Lys120fs)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
94003	NM_001918.5(DBT):c.51+1G>T	DBT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
94009	NM_001918.5(DBT):c.670G>T (p.Glu224Ter)	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts
94014	NM_001918.5(DBT):c.773-2A>G	DBT	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
DBT	Definitive	Autosomal recessive	maple syrup urine disease type 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DBT	Orphanet:268145	Classic maple syrup urine disease
DBT	Orphanet:268162	Intermediate maple syrup urine disease
DBT	Orphanet:268173	Intermittent maple syrup urine disease
DBT	Orphanet:268184	Thiamine-responsive maple syrup urine disease

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
DBT	HGNC:2698	ENSG00000137992	P11182	Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DBT	Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial	The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2).

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)
DBT	Enzyme (other)	yes	2.3.1.168	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS

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
buccal mucosa cell	1
endothelial cell	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DBT	290	ubiquitous	marker	buccal mucosa cell, renal medulla, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DBT	3,393

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DBT	P11182	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD	1	3806.7×	7e-04	DBT
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	1	2855.0×	7e-04	DBT
Loss-of-function mutations in DBT cause MSUD2	1	2855.0×	7e-04	DBT
Loss-of-function mutations in DLD cause MSUD3/DLDD	1	2855.0×	7e-04	DBT
Branched-chain ketoacid dehydrogenase kinase deficiency	1	2284.0×	7e-04	DBT
H139Hfs13* PPM1K causes a mild variant of MSUD	1	2284.0×	7e-04	DBT
Protein lipoylation	1	1038.2×	0.001	DBT
Branched-chain amino acid catabolism	1	475.8×	0.003	DBT
RHOH GTPase cycle	1	308.6×	0.004	DBT
Mitochondrial protein degradation	1	114.2×	0.009	DBT

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
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	1	4213.0×	5e-04	DBT
branched-chain amino acid catabolic process	1	1053.2×	9e-04	DBT

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
DBT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DBT	2.3.1.168	dihydrolipoyllysine-residue (2-methylpropanoyl)transferase

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	1	DBT
D	Druggable family + AlphaFold only, no drug	0
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)
DBT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.