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

Coenzyme Q₁₀ (CoQ₁₀)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ₁₀ biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ₁₀ supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ₁₀ levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ₁₀ deficiency.

WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ₁₀ deficiency and/or cerebellar ataxia. CoQ₁₀ levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts.

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). CoQ₁₀ 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.

This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ₁₀ deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ₁₀ deficiency.