DLD

Chr 7AR

dihydrolipoamide dehydrogenase

Also known as: DLDD, DLDH, E3, GCSL, LAD, OGDC-E3, PHE3

NCBI Gene: 1738ENSG00000091140UniProt: P09622

This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Primary Disease Associations & Inheritance

Dihydrolipoamide dehydrogenase deficiencyMIM #246900
AR
486
ClinVar variants
109
Pathogenic / LP
0.01
pLI score
1
Active trials
Clinical Summary— DLD
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
109 Pathogenic / Likely Pathogenic· 135 VUS of 486 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.55LOEUF
pLI 0.010
Z-score 3.42
OE 0.31 (0.19–0.55)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.10Z-score
OE missense 0.81 (0.73–0.91)
220 obs / 270.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.31 (0.19–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.73–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 9 / 28.8Missense obs/exp: 220 / 270.9Syn Z: -0.34

ClinVar Variant Classifications

486 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic66
VUS135
Likely Benign210
Benign23
Conflicting9
43
Pathogenic
66
Likely Pathogenic
135
VUS
210
Likely Benign
23
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
1
29
0
43
Likely Pathogenic
52
2
12
0
66
VUS
1
109
20
5
135
Likely Benign
0
2
99
109
210
Benign
0
0
23
0
23
Conflicting
—9
Total66114183114486

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DLD · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DLD-related dihydrolipoamide dehydrogenase E3 deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Dihydrolipoamide dehydrogenase deficiency

MIM #246900

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — DLD
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical practice guideline: Interventions for Developmental Language Delay and Disorders.
Neumann K et al.·Dtsch Arztebl Int
2024Guideline
How We Fail Children With Developmental Language Disorder.
McGregor KK·Lang Speech Hear Serv Sch
2020Review
Language intervention in bilingual children with developmental language disorder: A systematic review.
Kk Nair V et al.·Int J Lang Commun Disord
2023Review
Understanding Dyslexia in the Context of Developmental Language Disorders.
Adlof SM et al.·Lang Speech Hear Serv Sch
2018Review
An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.
Kurland G et al.·Am J Respir Crit Care Med
2013Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Diallyl Trisulfide From Garlic Regulates RAB18 Phase Separation to Inhibit Lipophagy and Induce Cuproptosis in Hepatic Stellate Cells for Antifibrotic Effects.
Tian H et al.·Adv Sci (Weinh)
2025
Editorial Perspective: Maximising the benefits of intervention research for children and young people with developmental language disorder (DLD) - a call for international consensus on standards of reporting in intervention studies for children with and at risk for DLD.
Frizelle P et al.·J Child Psychol Psychiatry
2023
Lipoic acid biosynthesis defects.
Mayr JA et al.·J Inherit Metab Dis
2014Review
Clinical associations between exercise and lipoproteins.
Mendoza MF et al.·Curr Opin Lipidol
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
DLD, upregulated by YY1, fuels glioblastoma multiforme progression via EphA2 phosphorylation to activate PI3K/AKT/mTOR.
Tang G et al.·QJM
2026
Evaluation of mdh, dld, tcfA, and folE gene markers for detection of enteric fever using real-time PCR.
Arshad S et al.·Sci Rep
2026
A short-term longitudinal study on the development of agreement in Italian: Syntactic configurations and non-word repetition as predictors of grammatical development in monolingual, bilingual and children with DLD.
Smith G et al.·Clin Linguist Phon
2026Natural history
Study of blood linear RNA nominates CD55 and DLD as early-stage biomarkers for Parkinson's sisease.
Beric A et al.·Brain
2026
The Interplay Between Language, Executive Functioning, Theory of Mind and Socio-Emotional Functioning - A Comparison Between Adolescents With and Without DLD.
Arts E et al.·Int J Lang Commun Disord
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Interstitial Lung Diseases of ChildhoodGenetic Testing

Genetic Causes and Clinical Features of Childhood Interstitial Lung Diseases in China

ACTIVE NOT RECRUITING
NCT03869515Children's Hospital of Fudan UniversityStarted 2019-03-25
No intervention

External Resources

Links to major genomics databases and tools