Hereditary neuropathy or pain disorder

Gene: DHTKD1

I don't know

Comment on list classification: While there are several patients reported with CMT and DHTKD1 variants (including the recurrent p.Tyr485Ter variant), the variants are of uncertain significance, and evidence for the association is limited. A knock in Dhtkd1 Y486* mouse model showed some signs of neuropathy on histology, but the motor performance was normal in the mutant mice. As reviewed by James Polke, high frequency of LOF variants in gnomAD and lack of a phenotype in carriers of AAKAD can be seen as refuting evidence. Hence, this gene should be downgraded from Green to Amber at the next GMS update.

Created: 27 Jul 2026, 9:18 a.m. | Last Modified: 27 Jul 2026, 9:18 a.m.

Panel Version: 8.12

PMID: 41169655 Başdemirci et al., 2025
Cohort of 58 patients with suspected CMT. Method: MLPA + NGS.
Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1.

PMID: 37880984 Menon et al., 2024
Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter.

PMID: 35052424 Osmanovic et al., 2021
Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.

PMID: 32169121 Luan et al. 2020 - Knock-in mouse model Dhtkd1 Y486* - partially recapitulated the clinical phenotypes of CMT2Q patients. Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice; histopathological phenotype was reminiscent of a peripheral neuropathy (reduced large axon diameter and abnormal myelination in peripheral nerves); mice displayed clear sensory defects, while no abnormalities in the motor performance were observed; also observed accumulation of mitochondria and an elevated energy metabolic state.

Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail:
https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13.

Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).

https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified).

Created: 27 Jul 2026, 7:59 a.m. | Last Modified: 27 Jul 2026, 8:50 a.m.

Panel Version: 8.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025; Charcot-Marie-Tooth disease axonal type 2Q, MONDO:0014012

Publications

• 32169121
• 35052424
• 37880984
• 41169655

Red List (low evidence)

This gene should not be 'Green' as a dominant cause of neuropathy in R78. The high frequency of LOF variants in gnomAD, lack of a phenotype in carriers of AAKAD (OMIM #204750), and lack of strong evidence as a cause of CMT2 argue against this.

PMID 34571524: Reports two heterozygous missense variants in DHTKD1 and a missense VUS in NTRK2 in a patient with a mitochondrial phenotype. Extremely weak evidence for this gene being related to CMT2Q

PMID 29661920: Homozygous knockout DHTKD1 mouse. Has symptoms of neuropathy alongside metabolic phenotype. No discussion of a phenotype in heterozygous knockout mice. Not strong evidence towards a dominant effect of LOF variants in humans.

PMID 28902413: Panel based NGS of 612 Neuropathy patients. I het null variant found in DHTKD1. Variant reported was prev. published as a recessive cause of AAKAD. PMID 25860818. No mention of parental phenotypes in this paper (or any other AAKAD cases that we have found). Too frequent in gnomAD (10-12094222-G-T - x166 hets in gnomAD v4.1.1) to be pathogenic dominantly. Should not contribute to Green classification for neuropathy.

Created: 8 Jun 2026, 4:47 p.m. | Last Modified: 8 Jun 2026, 4:47 p.m.

Panel Version: 8.4

Publications

• 34571524
• 29661920
• 28902413

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 9:32 a.m. | Last Modified: 2 May 2024, 9:32 a.m.

Panel Version: 4.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.

Created: 23 Aug 2023, 8:03 p.m. | Last Modified: 23 Aug 2023, 8:03 p.m.

Panel Version: 3.52

PMID:23141294 - Eight individuals from a 5-generation Chinese family were reported with Charcot-Marie-Tooth disease (CMT2) and heterozygous nonsense variant (p.Tyr485Ter) in the DHTKD1 gene.

PMID:28902413 - In this large cohort of 612 patients with hereditary neuropathies, one patient was identified with a monoallelic DHTKD variant.

PMID:34571524 - A 10 year-old male patient was reported with obesity, frequent falls, swollen legs and thighs, and pain in the lower and upper limbs. He was identified with heterozygous variants in DHTKD1 (associated with CMT2Q) and NTRK2 (associated with obesity, hyperphagia, and developmental delay).

PMID:29661920 - Studies on mouse models showed that Dhtkd1-/- mice mimic the major aspects of CMT2 phenotypes, characterized by progressive weakness and atrophy in the distal parts of limbs with motor and sensory dysfunctions, which are accompanied with decreased nerve conduction velocity.

Autosomal dominant variants in DHTKD1 gene has been associated with CMT2Q in OMIM (MIM #615025), but not yet associated with any phenotypes in Gene2Phenotype.

Created: 23 Aug 2023, 8:01 p.m. | Last Modified: 23 Aug 2023, 8:01 p.m.

Panel Version: 3.48

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025

Publications

• 23141294
• 28902413
• 29661920
• 34571524

I don't know

One multigenerational family reported plus another individual in a large CMT cohort; animal model. The variant reported in the Chinese family has been reported x1 gnomad, which does not necessarily make it 'benign'. Having said that, the gene is not constrained for LoF variants.

Created: 31 Mar 2020, 8:58 a.m. | Last Modified: 31 Mar 2020, 8:58 a.m.

Panel Version: 1.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease, axonal, type 2Q, MIM#615025

Publications

• 23141294
• 29661920
• 28902413

I don't know

Review and rating submitted by Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.

Created: 29 Apr 2019, 12:53 p.m.

Red List (low evidence)

Unable to find any evidence of clear neuropathy association

Created: 29 Apr 2019, 12:30 p.m.

Phenotypes
Charcot Marie Tooth disease, axonal, type 2Q, 615025; 2 aminoadipic 2 oxoadipic aciduria, 204750

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

only a single heterozygous nonsense mutation has been reorted in a large Chinese pedigree

Created: 9 Dec 2015, 4:47 p.m.

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

I think this gene should be removed from the panel. The original chinese family reported a lof het allele. LOF is not constrained in DHTKD!, more so recessive LOF variants in DHTKD1 cause Alpha-aminoadipic and alpha-ketoadipic aciduria and these patients do not have a peripheral neuropathy

Created: 20 Oct 2024, 9:35 a.m. | Last Modified: 20 Oct 2024, 9:35 a.m.

Panel Version: 5.19

Remove from panel, only single mutation reported was a non-sense mutation but this has been reported as a benign polymorphism in the heterozygous state.

Created: 9 Dec 2015, 8:49 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

Remove from panel, only single mutation reported was a non-sense mutation but this has been reported as a benign polymorphism in the heterozygous state.

Created: 8 Dec 2015, 3:05 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted