DHTKD1

Chr 10ADAR

dehydrogenase E1 and transketolase domain containing 1

Also known as: AAKAD, AMOXAD, CMT2Q, E1a, OADC-E1, OADH-E1

NCBI Gene: 55526 ENSG00000181192 UniProt: Q96HY7 OMIM: 614984

The protein functions as the 2-oxoadipate dehydrogenase component of the mitochondrial 2-oxoadipate dehydrogenase complex, catalyzing the rate-limiting decarboxylation of 2-oxoadipate in the final degradation pathway of lysine, hydroxylysine, and tryptophan. Mutations cause either alpha-aminoadipic and alpha-ketoadipic aciduria (a metabolic disorder) or Charcot-Marie-Tooth disease type 2Q (an axonal peripheral neuropathy), with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene shows relatively low constraint against loss-of-function variants, which may explain the variable clinical presentations and inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. [provided by RefSeq, May 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.252 OMIM phenotypes

Clinical Summary— DHTKD1

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Gene-Disease Validity (ClinGen)

2-aminoadipic 2-oxoadipic aciduria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

72 unique Pathogenic / Likely Pathogenic· 573 VUS of 1089 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.16

OE 0.97 (0.77–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.12Z-score

OE missense 1.01 (0.94–1.09)

539 obs / 531.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.97 (0.77–1.25)

0≤0.351.4

Missense OE?1.01 (0.94–1.09)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 46 / 47.2Missense obs/exp: 539 / 531.5Syn Z: -1.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDHTKD1-related 2-aminoadipic and 2-oxoadipic aciduriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5280th %ile

GOF

0.4974th %ile

LOF

0.4430th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFNotably, DHTKD1 Arg834* resulted in haploinsufficiency in the affected family members through nonsense-mediated decay (NMD).1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29669943 ↗

ClinVar Variant Classifications

1089 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39

Likely Pathogenic33

VUS573

Likely Benign341

Benign66

Conflicting16

Pathogenic

Likely Pathogenic

573

VUS

341

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	0	8	0	39
Likely Pathogenic	28	2	3	0	33
VUS	6	515	46	6	573
Likely Benign	0	12	125	204	341
Benign	1	3	53	9	66
Conflicting	—				16
Total	66	532	235	219	1,068

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap DHTKD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →