Case Report: Pediatric nephrology—expanding the genotypic spectrum of COQ2-related nephropathy with a novel splice site variant in CoQ10-responsive SRNS

Coenzyme Q10, also known as CoQ10, CoQ, and ubiquinone is an essential component of the mitochondrial electron-transport chain and functions as an energy transfer molecule as well as a redox carrier and is a lipid-soluble antioxidant. Biallelic pathogenic variants in one of the 10 genes encoding proteins involved in its synthesis, establishes the diagnosis of primary CoQ10 deficiency. <i>COQ2</i>, or parahydroxybenzoate-polyprenyltransferase (EC 2.5.1.39), catalyzes one of the final reactions in the biosynthesis of CoQ, the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. <i>COQ2</i> related CoQ10 deficiency can present with multiple system atrophy, cardiomyopathy and steroid resistant nephrotic syndrome (SRNS). Multiple papers have suggested CoQ supplement can treat SRNS. We report a 9-year-old girl presenting with steroid-resistant nephrotic syndrome, whose renal biopsy revealed focal segmental glomerulosclerosis. She showed only a partial response to combined therapy with tacrolimus, lisinopril, and losartan. Whole exome sequencing identified two compound heterozygous variants in the <i>COQ2</i> gene (NM_015697.7): a known pathogenic variant, c.683A>G, inherited from her father, and a novel splice-site variant, c.692+3A>G, inherited from her mother and currently classified as a variant of uncertain significance (VUS). Notably, previously reported patients carrying the c.683A>G variant typically present with early-onset, severe disease. In contrast, our patient's relatively late onset and isolated nephropathy suggests that the novel variant may be pathogenic but associated with a milder phenotype. Prompt genetic diagnosis enabled early initiation of high-dose CoQ10 supplementation (ubiquinone, 30 mg/kg/day), which led to marked clinical improvement and may have prevented further renal function deterioration or the development of other systemic manifestations.