Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder

- The PEX3 variant c.206-1G > T causes a milder Zellweger spectrum disorder phenotype than expected due to activation of a cryptic splice site.
- Genetic and functional studies of peroxisomes were required to reveal the peroxisome biogenesis disorder in the reported patients, as regular metabolic screening was normal.

Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype.