DHTKD1

Chr 10ADAR

dehydrogenase E1 and transketolase domain containing 1

NCBI Gene: 55526 ENSG00000181192 UniProt: Q96HY7

2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC) (PubMed:29191460, PubMed:29752936, PubMed:32303640, PubMed:32633484, PubMed:32695416). Participates in the first step, rate limiting for the overall conversion of 2-oxoadipate (alpha-ketoadipate) to glutaryl-CoA and CO(2) catalyzed by the whole OADHC (PubMed:29191460, PubMed:32695416). Catalyzes the irreversible decarboxylation of 2-oxoadipate via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST) (Probable) (PubMed:29752936, PubMed:32303640, PubMed:32633484). Can catalyze the decarboxylation of 2-oxoglutarate in vitro, but at a much lower rate than 2-oxoadipate (PubMed:29191460, PubMed:29752936, PubMed:32633484, PubMed:32695416). Responsible for the last step of L-lysine, L-hydroxylysine and L-tryptophan catabolism with the common product being 2-oxoadipate (Probable)

Primary Disease Associations & Inheritance

?Charcot-Marie-Tooth disease, axonal, type 2QMIM #615025

Alpha-aminoadipic and alpha-ketoadipic aciduriaMIM #204750

580

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

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

46 Pathogenic / Likely Pathogenic· 348 VUS of 580 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

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?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.

-0.12Z-score

OE missense 1.01 (0.94–1.09)

539 obs / 531.5 exp

Tolerant

Tolerant to missense variation

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.0.97 (0.77–1.25)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.94–1.09)

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.1.10

0≤1.21.6

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