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.
Keywords: ES, exome sequencing; GS, genome sequencing; Genetic testing; Genome sequencing; IRD, infantile Refsum disease; MAF, minor allele frequency; NALD, neonatal adrenoleukodystrophy; PBD, peroxisome biogenesis disorder; PEX3; PMP, peroxisomal membrane protein; Peroxisome biogenesis disorder; RCDP, rhizomelic chondrodysplasia punctata; VLCFA, very-long chain fatty acids; X-ALD, X-linked adrenoleukodystrophy; ZS, Zellweger syndrome; ZSD, Zellweger spectrum disorder; Zellweger spectrum disorder; gnomAD, Genome Aggregate Database.
© 2020 The Authors.