Likely inborn error of metabolism - targeted testing not possible
Gene: PDK3
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
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
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
Variants in this GENE are reported as part of current diagnostic practice
At least 1 variant reported. Phenotype associated with Charcot-Marie-Tooth Disease in humans, not in G2P. Cellular response to glucose in rats onlyCreated: 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
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Tag Q1_22_phenotype was removed from gene: PDK3. Tag Q2_22_rating was removed from gene: PDK3. Tag Q2_22_expert_review was removed from gene: PDK3.
Source Expert Review Green was added to PDK3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q2_22_rating tag was added to gene: PDK3.
Tag Q2_22_expert_review tag was added to gene: PDK3.
Publications for gene: PDK3 were set to 27604308; 26801680; 28902413; 23297365
Tag Q1_22_phenotype tag was added to gene: PDK3.
Gene: pdk3 has been classified as Amber List (Moderate Evidence).
Mode of pathogenicity for gene: PDK3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Publications for gene: PDK3 were set to 27604308; 26801680; 28902413
Publications for gene: PDK3 were set to 27604308
Phenotypes for gene: PDK3 were changed from ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905; ?Charcot-Marie-Tooth disease, X-linked dominant, 6, 300905; Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism) to ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905
Source NHS GMS was added to PDK3. Source London North GLH was added to PDK3.
Sarah Leigh: Associated with phenotype in O
Added phenotypes ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905; Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism) for gene: PDK3 Publications for gene PDK3 were changed from to 27604308
gene: PDK3 was added gene: PDK3 was added to Inborn errors of metabolism. Sources: Expert Review Red Mode of inheritance for gene: PDK3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: PDK3 were set to ?Charcot-Marie-Tooth disease, X-linked dominant, 6, 300905