Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and updated literature review

Loss-of-function mutations in PEX3 have been associated with Zellweger syndrome (ZS), a severe form of peroxisome biogenesis disorder (PBD) characterized by significant global developmental delay, muscle weakness with bilateral ptosis, cholestasis, hypotonia, and seizures. ZS can be life-threatening if manifested in the neonatal period. This study presents a unique case of a male infant with severe ZS whose condition deteriorated despite intensive supportive treatment. Through whole-exome sequencing, an intronic variant NM_003630.2:c.288-10T > A, located 10 nucleotides before exon 4 of the PEX3 gene, was identified. Sanger sequencing revealed a homozygous variant in the infant and a heterozygous variant in both parents. Further analysis confirmed the abnormal transcript of the PEX3 gene caused by a frameshift variant resulting from the PEX3 gene c.288-10T > A mutation. This modification led to a splicing error that deleted exon 4, causing a direct splicing of exons 3 and 5. This alteration produced a truncated protein comprising 32 incorrect amino acids. We systematically summarized common phenotypes across 10 reported PEX3-related Zellweger spectrum disorder (ZSD) cases (including the current patient): profound global developmental delay (9/10), bilateral ptosis/ocular motility dysfunction (7/10), and hypotonia (7/10). These consistent phenotypes reflect genotype-phenotype correlation in PEX3-related ZSD, providing valuable clues for early clinical suspicion and diagnosis. We report the first Chinese case of severe ZSD caused by the PEX3 variant [c.288-10T > A: p.P97Ffs*33], broadening the spectrum of severe ZSDs associated with pathogenic PEX3 variants. Our summary of 10 PEX3-related ZSD cases identifies three core phenotypes—profound global developmental delay, bilateral ptosis, and hypotonia—that aid early clinical suspicion and targeted genetic testing.