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…

Primary Disease Associations & Inheritance

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

Alpha-aminoadipic and alpha-ketoadipic aciduriaMIM #204750

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · 2-aminoadipic 2-oxoadipic aciduria · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.25

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in DHTKD1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

1,322 rare PASS variants

Rare truncating (LoF)

1 in 540

187 rare PASS variants

Rare synonymous (reference)

1 in 86

478 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DHTKD1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 530
South Asian	~43k	1 in 37	1 in 540
Remaining (unassigned)	~30k	1 in 42	1 in 370
European (Finnish)	~27k	1 in 77	1 in 1,700
Admixed American	~22k	1 in 47	1 in 730
African / African American	~21k	1 in 39	1 in 520
East Asian	~20k	1 in 36	1 in 320
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 45	1 in 560

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 17 coding exons well covered in gnomAD exomes; exons 9, 14 marginal. Genomes: 16 of 17 (exon 9 below).? see exons ↓