A nonsense variant in PEX5 is associated with an atypical peroxisome biogenesis disorder and retinitis pigmentosa.

Abstract

Purpose : This study aimed to provide a genetic diagnosis for patients presenting with a mild peroxisome biogenesis disorder (PBD). Peroxisomes play a vital role in a variety of metabolic processes including β-oxidation of fatty acids and glyoxylate detoxification. Pathogenic variants in 13 PEX genes have been associated with PBDs. Clinical features vary but can include failure to thrive, developmental delay, retinal degeneration and liver disease. PEX5 encodes a peroxisomal import receptor protein and two isoforms exist in humans: PEX5S and PEX5L, the latter contains an additional exon.

Methods : Two affected siblings were recruited to the Target 5000 inherited retinal disease (IRD) study following a clinical diagnosis of PBD with retinitis pigmentosa. An unaffected sibling was also recruited. Targeted sequencing of the exons of 254 IRD genes was carried out on one affected sibling. Subsequently whole genome sequencing (WGS) was employed on the same individual as a more comprehensive sequencing measure.

Results : At last examination the patients were in their 8^th and 9^th decades of life. Following targeted sequencing no candidate variants were detected. WGS revealed a homozygous nonsense variant in PEX5, c.709C>T, p.(Arg237Ter), situated in the exon specific to PEX5L, leaving PEX5S unperturbed at the DNA level. This variant was present homozygously in both affected siblings while the unaffected sibling was homozygous for the wild-type base at this position. Pathogenic variants in PEX5 are typically associated with phenotypically severe PBDs. These patients did not display classical symptoms associated with a PEX5 defect including reduced life expectancy, epilepsy, growth delay or intellectual disability.

Conclusions : To the best of our knowledge, this is the first report of a significantly milder form of PBD than typically associated with PEX5 defects suggesting that the severity of the phenotype depends on the location of the given variant. Awareness of this unusual clinical presentation will allow for a more targeted diagnostic approach. This study highlights the value of WGS over targeted sequencing, where only the former was informative in terms of disease pathogenesis. The findings also underscore the importance of interrogating genes typically associated with more severe forms of disease even when the clinical presentation is relatively mild by comparison.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.