Likely inborn error of metabolism

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, 10:24 a.m. | Last Modified: 1 Feb 2023, 10:24 a.m.

Panel Version: 3.6

At least two variants in three unrelated families reported (founder effect ruled out). Functional analyses conducted in patient fibroblasts, cell lines, and in vivo animal model (C. elegans) show that the recurrent variant (p.R158H) increased phosphorylation of the pyruvate dehydrogenase complex and thereby leads to significant reductions in ATP levels. Abnormal mitochondrial networks and mitochondrial trafficking were also reduced in affected axons.

Although energy metabolism defects and mitochondrial abnormalities are observed, the CMT phenotype presented by patients may not be relevant to this panel. For this reason, inclusion of PDK3 will be reviewed by the test evaluation group at the next GMS panel update.

Created: 5 Jan 2022, 12:40 p.m. | Last Modified: 5 Jan 2022, 12:40 p.m.

Panel Version: 2.212

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, OMIM:300905

Publications

• 23297365
• 26801680
• 27388934
• 28902413
• 32504000
• 34387338

Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least three unrelated cases, together with functional studies.
The phenotype of ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905, is not relevant to the "Inborn errors of metabolism" panel, which is why it is rated Amber (clinical opinion of Helen Britain, GEL Clinical Fellow).

Created: 27 Sep 2019, 4:28 p.m. | Last Modified: 12 Dec 2019, 12:22 p.m.

Panel Version: 1.425

Comment on mode of pathogenicity: A gain of function mechanism has been reported for the p.R158H variant, resulting in a more activity than the wild-type kinase (PMID: 23297365).

Created: 27 Sep 2019, 3:54 p.m. | Last Modified: 27 Sep 2019, 3:54 p.m.

Panel Version: 1.312

Comment on phenotypes: Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism)

Created: 27 Sep 2019, 2:41 p.m. | Last Modified: 27 Sep 2019, 2:41 p.m.

Panel Version: 1.309

I don't know

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, MIM#300905

Publications

• 26801680
• 28902413

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

Red List (low evidence)

At least 1 variant reported. Phenotype associated with Charcot-Marie-Tooth Disease in humans, not in G2P. Cellular response to glucose in rats only

Created: 23 Feb 2017, 5:15 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

Green List (high evidence)

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