Hereditary neuropathy or pain disorder

Gene: PDK3

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 10:16 a.m. | Last Modified: 7 Jan 2024, 7:44 p.m.

Panel Version: 3.74

Green List (high evidence)

Comment on list classification: At least two variants in three unrelated families reported (founder effect ruled out), as well as functional analyses conducted in patient fibroblasts, cell lines, and animal model. This supports a rating upgrade on this panel from Amber to Green at the next GMS panel update (tagged).

Created: 5 Jan 2022, 12:15 p.m. | Last Modified: 5 Jan 2022, 12:15 p.m.

Panel Version: 1.79

Narayanan et al., 2021 (PMID: 34387338) developed a C. elegans model of CMTX6 by knocking-in the p.R158H variant in the orthologous PDK3 gene and by expressing the mutant form of human PDK3 specifically in the GABAergic motor neurons of C. elegans. Mutants exhibited axon-associated synaptic transmission deficits, locomotion defects, signs of progressive neurodegeneration and also displayed ATP deficits that recapitulate phenotypes observed in patient fibroblasts and iPSC-derived motor neurons.

Created: 5 Jan 2022, noon | Last Modified: 5 Jan 2022, noon

Panel Version: 1.78

Phenotypes
Charcot-Marie-Tooth disease, X-linked dominant, 6, OMIM:300905

Publications

• 34387338

Green List (high evidence)

One Australian, one Korean family identified with same variant. Additional case reported in a cohort of neuropathy patients, different variant. Some functional data.

Created: 1 Apr 2020, 9:30 a.m. | Last Modified: 1 Apr 2020, 9:30 a.m.

Panel Version: 1.4

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Charcot-Marie-Tooth disease, X-linked dominant, 6 MIM#300905; HMSN

Publications

• 23297365
• 26801680
• 27388934
• 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.

I don't know

2 families and some functional work. PMID: 23297365 (Kennerson et al, 2013) Australian family appears to segregateand some functional work; PMID: 26801680 (Kennerson et al, 2016) Korean family

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

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
?Charcot Marie Tooth disease, X linked dominant, 6, 300905

Publications

• 23297365
• 26801680

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

Green List (high evidence)

Comment on list classification: Await further evidence before promote to green list

Created: 8 Jul 2016, 4:01 a.m.

Comment on publications: Two families have now been reported with the p.R158H mutation, though this is still not enough evidence to be rated green, with only one known Charcot-Marie-Tooth disease-causing variant in this gene reported to date.

Created: 5 May 2016, 9:22 a.m.

Comment on mode of inheritance: Seems to be X-linked dominant (monoallelic mutations in females could cause the disorder).

Created: 5 May 2016, 9:19 a.m.

I don't know

Now 2 families, likely pathogenic

Created: 16 May 2019, 4:21 p.m.

Single family

Created: 9 Dec 2015, 8:50 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Red List (low evidence)

Single family

Created: 8 Dec 2015, 3:06 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females