Genome sequencing identifies a rare case of moderate Zellweger spectrum disorder caused by a PEX3 defect: Case report and literature review

• Published in: Molecular genetics and metabolism reports 2020-12, Vol.25, p.100664, Article 100664
• Main Authors: Lee, Whiwon, Costain, Gregory, Blaser, Susan, Walker, Susan, Marshall, Christian R., Gonorazky, Hernan, Inbar-Feigenberg, Michal
• Format: Article
• Language: English
• Subjects: Case Report; Genetic testing; Genome sequencing; Peroxisome biogenesis disorder; PEX3; Zellweger spectrum disorder
• ISSN: 2214-4269; 2214-4269
• DOI: 10.1016/j.ymgmr.2020.100664

Defects in PEX3 are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical phenotypes expand the reported spectrum of PEX3-related disease. Genome sequencing of an adolescent male with progressive movement disorder, spasticity and neurodegeneration, and previous non-diagnostic plasma very-long chain fatty acid analysis, revealed a homozygous likely pathogenic missense variant in PEX3 [c.991G > A; p.(Gly331Arg)]. A younger sibling with significant motor decline since the age of three years was also subsequently found to be homozygous for the familial PEX3 variant. A comprehensive review of the scientific literature identified three additional families with non-lethal infantile- or childhood-onset PEX3-related disease, which together with this clinical report illustrate the potential for highly variable disease severity. Our findings demonstrate the diagnostic utility of genome-wide sequencing for identifying clinically and biochemically heterogeneous inherited metabolic disorders such as the peroxisome biogenesis disorders.