Submission Details

The relationship between PDSS1 and PDSS1-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2023. The PDSS1 gene encodes prenyl diphosphate synthase subunit 1, an enzyme that supplies decaprenyl diphosphate, the precursor for the side chain of the isoprenoid quinone Coenzyme Q10 that functions as a mobile electron carrier in the respiratory chain, as well as other mitochondrial functions including antioxidant properties. A heterodimer is formed by PDSS1 and PDSS2 that functions to isoprenylate benzoquinone in the CoQ10 biosynthesis pathway.

The PDSS1 gene was first reported in relation to PDSS1-related primary mitochondrial disease in 2007 (PMID: 17332895). PDSS1 has been associated with a single disease entity to date, autosomal recessive primary Coenzyme Q10 deficiency 2 [OMIM# 614651]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as PDSS1-related primary mitochondrial disease.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (four missense, two termination) identified in four unrelated cases from four publications (PMIDs: 17332895, 22494076, 34765390, 33285023). Age of onset was early childhood and clinical features in affected individuals include hearing loss, optic atrophy, encephalopathy, livedo reticularis, peripheral neuropathy, nephrotic syndrome, renal failure, pulmonary hypertension, and mild intellectual disability. Brain imaging showed white matter changes and metabolic screening labs showed elevated lactate and decreased Coenzyme Q10. Of note, this expert panel elected to exclude the cases summarized in Jurkute et al., 2022 (PMID: 36266294) given the notable difference in phenotypes reported in this cohort (retinitis pigmentosa and variable hearing loss) and lack of functional evidence providing support for this more mild presentation.

The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with coenzyme Q10 biosynthetic defects and a Drosophila melanogaster model (PMIDs: 17332895, 20889762).

In summary, there is moderate evidence to support the relationship between PDSS1 and PDSS1-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 31, 2023 (SOP Version 10).