Submission Details

The relationship between PDHX and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 17, 2024. The PDHX gene encodes the E3 binding protein of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, and is thus the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism.

PDHX was first reported in relation to autosomal recessive primary mitochondrial disease in 1997 (PMID: 9399911). While various names have been given to the constellation of features seen in those with PDHX-related disorders, including pyruvate dehydrogenase complex deficiency or PDCD, pathogenic variants in this gene ultimately cause a primary mitochondrial disease. Therefore, the PDHX phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, PDHX was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on July 13, 2020 (SOP V7), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation.

Evidence supporting the relationship between PDHX and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes seven variants identified in six unrelated probands in six publications (PMIDs: 12557299, 14518830, 15303005, 16566017, 25087164, 27343776). Variants reported include nonsense, splicing, and frameshift. There is a Roma founder variant, NM_003477.3:c.1336C>T (p.Arg446Ter), and a Moroccan founder variant (NM_003477.3:c.1182+2T>C (p.Ile386SerfsTer13). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Age of onset ranged from the first days of life to later in childhood, with some individuals living well into adulthood. Clinical features in affected individuals include neonatal lactic acidosis, LSS, seizures, spasticity, agenesis of the corpus callosum, cerebral atrophy, vomiting, and optic atrophy. PDC enzyme activity was reduced in fibroblasts.

The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of the E3 binding protein in supporting PDC activity, and functional alteration in patient cells (PMIDs: 14518830, 11935326, 20002125).

In summary, there is definitive evidence to support the relationship between PDHX and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 17, 2024 (SOP Version 11).