Year: 2025
Type: article
Abstract: Introduction Primary coenzyme Q10 deficiency is a rare mitochondrial disorder with multisystem involvement, often undiagnosed in prenatal stages due to phenotypic variability and ambiguous genetic findings. Here, we report a prenatal case of primary coenzyme Q10 deficiency Type 1 diagnosed via 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 have identified compound heterozygous COQ2 variants in a fetus with severe growth restriction. Pathogenicity is confirmed via minigene splicing assays and yeast complementation. Results Minigene splicing assays demonstrated that the c.779-2A>G splice-site variant induces complete exon 5 skipping, generating a frameshift truncation (p.Leu261Glnfs*4) that abolishes the polyprenyltransferase domain. Functional studies in coq2Δ yeast revealed that both alleles impair respiratory growth, with the truncation variant (c.779-2A>G) showing complete loss of function, while 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 due to disrupted hydrogen bonds (Thr325- Gly322/His303). Conclusion This study provides 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 to <0.00001 globally. This study expands the screening spectrum of COQ2 and provide mechanistic insights into genotype-phenotype correlations in primary coenzyme Q10 deficiency.
Source: Kidney International Reports
Authors: Zhanqi Feng, Liangjie Guo, Yue Gao, Mengting Zhang, Xiuming Liu, Bing Kang, Mengyao Tan, Shixiu Liao, Hongdan Wang
Institutions: Zhengzhou University, Henan Provincial People's Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
Funders: Health Commission of Henan Province, National Natural Science Foundation of China, Natural Science Foundation of Henan Province, Science and Technology Department, Henan Province, National Health Commission of the People's Republic of China, Henan Provincial Science and Technology Research Project
OpenAlex ID: W4413676828