pyruvate dehydrogenase E1-beta deficiency

Summary

pyruvate dehydrogenase E1-beta deficiency (MONDO:0013580) is a disease caused by PDHB (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PDHB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 359
• Phenotypes (HPO): 23
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002683	Abnormality of the calvaria	Frequent (30-79%)
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0004325	Decreased body weight	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002365	Hypoplasia of the brainstem	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)
HP:0007016	Corticospinal tract hypoplasia	Occasional (5-29%)
HP:0007109	Periventricular cysts	Occasional (5-29%)
HP:0007165	Periventricular heterotopia	Occasional (5-29%)
HP:0007772	Impaired smooth pursuit	Occasional (5-29%)
HP:0200012	Short corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyruvate dehydrogenase E1-beta deficiency
Mondo ID	MONDO:0013580
MeSH	C566729
OMIM	614111
Orphanet	255138
UMLS	C3279841
MedGen	481471
GARD	0017236
Is cancer (heuristic)	no

Also known as: PDHBD · pyruvate dehydrogenase complex E1 component subunit beta deficiency · pyruvate dehydrogenase E1-beta deficiency

Data availability: 359 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › pyruvate dehydrogenase deficiency › pyruvate dehydrogenase E1-beta deficiency

Related subtypes (6): pyruvate dehydrogenase E2 deficiency, pyruvate dehydrogenase E3-binding protein deficiency, pyruvate dehydrogenase E3 deficiency, pyruvate dehydrogenase E1-alpha deficiency, pyruvate dehydrogenase phosphatase deficiency, lipoic acid synthetase deficiency

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

359 retrieved; paginated sample, class counts are floors:

233 likely benign, 57 uncertain significance, 17 benign, 17 pathogenic, 15 likely pathogenic, 11 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4747313	NM_000925.4(PDHB):c.42+1G>A	LOC129936949	Pathogenic	criteria provided, single submitter
13189	NM_000925.4(PDHB):c.1030C>T (p.Pro344Ser)	PDHB	Pathogenic	no assertion criteria provided
1984417	NM_000925.4(PDHB):c.122_123del (p.Gln41fs)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501782	NM_000925.4(PDHB):c.1A>G (p.Met1Val)	PDHB	Pathogenic	criteria provided, single submitter
2677598	NM_000925.4(PDHB):c.716_717del (p.Val239fs)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677600	NM_000925.4(PDHB):c.211C>T (p.Arg71Ter)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2732344	NM_000925.4(PDHB):c.238_239del (p.Lys80fs)	PDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2760571	NM_000925.4(PDHB):c.714dup (p.Val239fs)	PDHB	Pathogenic	criteria provided, single submitter
2799883	NM_000925.4(PDHB):c.495G>A (p.Trp165Ter)	PDHB	Pathogenic	criteria provided, single submitter
2834403	NM_000925.4(PDHB):c.803del (p.Met268fs)	PDHB	Pathogenic	criteria provided, single submitter
2853430	NM_000925.4(PDHB):c.231T>G (p.Tyr77Ter)	PDHB	Pathogenic	criteria provided, single submitter
2859779	NM_000925.4(PDHB):c.639_655del (p.Pro214fs)	PDHB	Pathogenic	criteria provided, single submitter
2961156	NM_000925.4(PDHB):c.478_479del (p.Gln160fs)	PDHB	Pathogenic	criteria provided, single submitter
3003908	NM_000925.4(PDHB):c.533_534delinsAA (p.Trp178Ter)	PDHB	Pathogenic	criteria provided, single submitter
3014800	NM_000925.4(PDHB):c.578del (p.Asp193fs)	PDHB	Pathogenic	criteria provided, single submitter
3677772	NM_000925.4(PDHB):c.692_695del (p.Glu231fs)	PDHB	Pathogenic	criteria provided, single submitter
4721142	NM_000925.4(PDHB):c.650dup (p.Ser218fs)	PDHB	Pathogenic	criteria provided, single submitter
4725125	NM_000925.4(PDHB):c.461dup (p.Ala155fs)	PDHB	Pathogenic	criteria provided, single submitter
839569	NM_000925.4(PDHB):c.301A>G (p.Met101Val)	PDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
978592	NM_000925.4(PDHB):c.494G>C (p.Trp165Ser)	PDHB	Pathogenic	no assertion criteria provided
978593	NM_000925.4(PDHB):c.302T>C (p.Met101Thr)	PDHB	Pathogenic	no assertion criteria provided
1463811	NM_000925.4(PDHB):c.96+2T>C	LOC129936949	Likely pathogenic	criteria provided, single submitter
2781131	NM_000925.4(PDHB):c.41_43-12del	LOC129936949	Likely pathogenic	criteria provided, single submitter
13188	NM_000925.4(PDHB):c.395A>G (p.Tyr132Cys)	PDHB	Likely pathogenic	criteria provided, single submitter
2413152	NM_000925.4(PDHB):c.121C>T (p.Gln41Ter)	PDHB	Likely pathogenic	criteria provided, single submitter
2445695	NM_000925.4(PDHB):c.818del (p.Pro273fs)	PDHB	Likely pathogenic	criteria provided, single submitter
2677595	NM_000925.4(PDHB):c.469C>T (p.Gln157Ter)	PDHB	Likely pathogenic	criteria provided, single submitter
2677597	NM_000925.4(PDHB):c.352C>T (p.Gln118Ter)	PDHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677599	NM_000925.4(PDHB):c.934+1G>A	PDHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677601	NM_000925.4(PDHB):c.607G>T (p.Glu203Ter)	PDHB	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PDHB	Strong	Autosomal recessive	pyruvate dehydrogenase E1-beta deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDHB	Orphanet:255138	Pyruvate dehydrogenase E1-beta deficiency

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
PDHB	HGNC:8808	ENSG00000168291	P11177	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial	gencc,clinvar
DNAH12	HGNC:2943	ENSG00000174844	Q6ZR08	Dynein axonemal heavy chain 12	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDHB	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial	Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.
DNAH12	Dynein axonemal heavy chain 12	Involved in spermiogenesis.

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)
PDHB	Enzyme (other)	yes	1.2.1.104	Transketolase-like_Pyr-bd, Transketo_C/PFOR_II, PDHB_mito-type
DNAH12	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dhc_linker

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
biceps brachii	1
endothelial cell	1
heart right ventricle	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDHB	299	ubiquitous	marker	endothelial cell, heart right ventricle, biceps brachii
DNAH12	174	tissue_specific	marker	bronchial epithelial cell, bronchus, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDHB	3,784
DNAH12	1,268

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDHB	P11177	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAH12	Q6ZR08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
PDH complex synthesizes acetyl-CoA from PYR	1	1631.4×	0.002	PDHB
Regulation of pyruvate dehydrogenase (PDH) complex	1	713.8×	0.003	PDHB
Signaling by Retinoic Acid	1	407.9×	0.003	PDHB
Mitochondrial protein degradation	1	114.2×	0.009	PDHB

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
pyruvate decarboxylation to acetyl-CoA	1	1053.2×	0.006	PDHB
axonemal dynein complex assembly	1	526.6×	0.006	DNAH12
tricarboxylic acid cycle	1	255.3×	0.006	PDHB
sperm axoneme assembly	1	234.1×	0.006	DNAH12
glucose metabolic process	1	127.7×	0.009	PDHB
spermatid development	1	72.6×	0.014	DNAH12

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
PDHB	0	0
DNAH12	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
PDHB	3	Binding:3
DNAH12	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDHB	1.2.1.104, 1.2.4.1	pyruvate dehydrogenase system, pyruvate dehydrogenase (acetyl-transferring)

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	PDHB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DNAH12

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)
PDHB	3	—
DNAH12	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
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency