Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype

Abstract

The aim of this study was to investigate coenzyme Q10 (CoQ10) biosynthesis pathway defects in inherited retinal dystrophy. Individuals affected by inherited retinal dystrophy (IRD) underwent exome or genome sequencing for molecular diagnosis of their condition. Following negative IRD gene panel analysis, patients carrying biallelic variants in CoQ10 biosynthesis pathway genes were identified. Clinical data were collected from the medical records. Haplotypes harbouring the same missense variant were characterised from family genome sequencing (GS) data and direct Sanger sequencing. Candidate splice variants were characterised using Oxford Nanopore Technologies single molecule sequencing. The CoQ10 status of the human plasma was determined in some of the study patients. 13 individuals from 12 unrelated families harboured candidate pathogenic genotypes in the genes: PDSS1, COQ2, COQ4 and COQ5. The PDSS1 variant c.589 A > G was identified in three affected individuals from three unrelated families on a possible ancestral haplotype. Three variants (PDSS1 c.468-25 A > G, PDSS1 c.722-2 A > G, COQ5 c.682-7 T > G) were shown to lead to cryptic splicing. 6 affected individuals were diagnosed with non-syndromic retinitis pigmentosa and 7 had additional clinical findings. This study provides evidence of CoQ10 biosynthesis pathway gene defects leading to non-syndromic retinitis pigmentosa in some cases. Intronic variants outside of the canonical splice-sites represent an important cause of disease. RT-PCR nanopore sequencing is effective in characterising these splice defects.

VIsoQLR: an interactive tool for the detection, quantification and fine-tuning of isoforms in selected genes using long-read sequencing

“…On the other hand, short-read sequencing of RT-PCR products can be used to discover splicing sites, but cannot determine the exon organization of the full-length isoforms. The recent advent of long-read sequencing (LRS) appears as an alternative to characterize and quantify the isoform spectrum in splicing assays (Amarasinghe et al 2020 ; Helman et al 2021 ; Dai et al 2022 ; Jurkute et al 2022 ). This latter approach has the potential to cover entire transcripts in a single read, allowing the study of splice sites and complete exon organization of all sequenced transcripts.…”

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

“…These findings suggests that the majority of CoQ 10 deficiency disorders share a common spectrum of neuropathology. Interestingly, also retinal affection seems to be a rare disease feature of many COQ defects (e.g., PDSS1, COQ2, COQ4 and COQ5) [ 66 ].…”

COQ4 is required for the oxidative decarboxylation of the C1 carbon of Coenzyme Q in eukaryotic cells

“…The COQ4 gene is relevant for human disease because its mutations are one of the most common causes of primary coenzyme Q deficiency 13 . They are associated with a variety of clinical pictures ranging from fatal neonatal multisystem disorders 14 , to childhood-onset cerebellar ataxia 15 , or isolated retinitis pigmentosa 16 . Interestingly, COQ4 patients usually display a lower response to oral CoQ 10 supplementation compared to patients with other COQ gene defects 17 , hence the importance of understanding the precise function of COQ4.…”