Hereditary neuropathy or pain disorder

Gene: DHTKD1

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