Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency

Abstract

Background and aims: Primary Coenzyme Q (CoQ) deficiency caused by COQ4 defects is a clinically heterogeneous mitochondrial condition characterized by reduced levels of CoQ10 in tissues. Next-generation sequencing has lately boosted the genetic diagnosis of an increasing number of patients. Still, functional validation of new variants of uncertain significance is essential for an adequate diagnosis, proper clinical management, treatment, and genetic counseling. Materials and methods: Both fibroblasts from a proband with COQ4 deficiency and a COQ4 knockout cell model have been characterized by a combination of biochemical and genetic analysis (HPLC lipid analysis, Oxygen consumption, minigene analysis, RNAseq, among others). Results: Here, we report the case of a subject harboring a new variant of the COQ4 gene in compound heterozygosis, which shows severe clinical manifestations. We present the molecular characterization of this new pathogenic variant affecting the splicing of COQ4. Conclusion: Our results highlight the importance of expanding the genetic analysis beyond the coding sequence to reduce the misdiagnosis of primary CoQ deficiency patients.