Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency

Background and Objectives Coenzyme Q(10) (CoQ(10))-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ(10) biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ(10) supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ(10) levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ(10) deficiency. Methods WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ(10) deficiency and/or cerebellar ataxia. CoQ(10) levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts. Results A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A (ADCK3) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found (COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ(10) levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect. Discussion This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ(10) deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ(10) deficiency.