Introduction: Primary coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder with multisystem involvement, often undiagnosed in prenatal stages because of phenotypic variability and ambiguous genetic findings. Here, we report a prenatal case of primary CoQ10 deficiency type 1 diagnosed using amniocentesis, identifying compound heterozygous COQ2 variants (a maternally inherited novel splice-site variant c.779-2A>G and paternally inherited c.973A>G) in a fetus exhibiting growth restriction and cardiac anomalies.

Methods: Through family-based whole-exome sequencing, we identified compound heterozygous COQ2 variants in a fetus with severe growth restriction. Pathogenicity was confirmed via minigene splicing assays and yeast complementation.

Results: Minigene splicing assays demonstrated that the c.779-2A>G splice-site variant induced complete exon 5 skipping, generating a frameshift truncation (p.Leu261Glnfs∗4) that abolished the polyprenyltransferase domain. Functional studies in coq2Δ yeast revealed that both alleles impaired respiratory growth, with the truncation variant (c.779-2A>G) showing complete loss of function, whereas the missense variant (c.973A>G) exhibited partial residual activity (OD600 = 0.52 vs. wild-type 0.59). Structural modeling of p.Thr325Ala highlighted destabilization of the substrate-binding pocket because of disrupted hydrogen bonds (Thr325- Gly322/His303).

Conclusion: To the best of our knowledge, this study provided the first experimental evidence for the hypomorphic nature of c.973A>G, observed in Asian cohorts with nephropathy but previously classified as a variant of uncertain significance. The variant has a minor allele frequency of 0.00071 in the gnomAD East Asian population, compared with < 0.00001 globally. This study expanded the screening spectrum of COQ2 and provided mechanistic insights into genotype-phenotype correlations in primary CoQ10 deficiency.

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Feng Z, Guo L, Gao Y, Zhang M, Liu X, Kang B, Tan M, Liao S, Wang H

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