Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum via the PEX6 Gene

Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (PBD-ZSS) consist of three related diseases Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum disease (IRD) that share overlapping phenotypes with severity ranging from ZS to IRD. The overall incidence of PBD-ZSS is estimated to be from 1:500,000 to 1:50,000 (Steinberg et al. 2012). Common clinical features to all three include neurodevelopmental delay, glaucoma, retinal dystrophy, impaired hearing, renal cysts, and hepatic dysfunction (Wanders and Waterham 2005). Zellweger syndrome (ZS) is the most severe with neonatal onset, and characterized by typical craniofacial dysmorphism and profound hypotonia, severe seizures, and inability to feed. Infants with ZS usually do not make any developmental progress and rarely survive the first year of life. Compared to ZS, patients with NALD have less severe hypotonia and seizures during infancy and may reach school age. IRD is the least severe form. Patients with IRD show variable developmental delay and often present predominantly with vision problems, sensorineural hearing loss, and liver dysfunction. Most affected patients can reach childhood and, in rare cases, survive into adulthood. It has been suggested that a peroxisome biogenesis disorder should be considered in any individuals manifesting both vision and hearing problems. Biochemical findings of a PBD-ZSS patient include elevated plasma VLCFAs (C24:0 and C26:0), phytanic acid, and pipecolate and deficient plasmalogen synthesis in erythrocytes or cultured fibroblasts. A disparity of biochemical results obtained from different specimens (plasma, cultured cells or tissues) has been reported in milder patients due to peroxisomal mosaicism. Treatments of PBD-ZSS focus on symptomatic therapy (Steinberg et al. 2012; Steinberg et al. 2006).

PBD-ZSS are all autosomal recessively inherited and caused by pathogenic variants in one of the PEX genes required for normal peroxisome assembly and/or peroxisomal protein import. The clinical severity is generally correlated with the impact of a given mutation on peroxisome formation and function (Ebberink et al. 2011). At least 13 PEX genes have been reported to be involved with PBD-ZSS (Smith and Aitchison 2013).

PEX6, a cytosolic protein, interacts with PEX1 and plays an important role in vesicle fusion and import of peroxisomal proteins. After PEX1, PEX6 is the second most affected gene among patients with PBD-ZSS (approximately 11-16%). Reported PEX6 pathogenic variants are scattered throughout all coding exons but commonly found in exon 1, including missense, nonsense, splicing site mutations, small deletion/insertions, and large deletions (Steinberg et al. 2004; Waterham and Ebberink 2012).

In two separate cohorts of PBD-ZSS patients, 11-16% of affected patients were identified with causative PEX6 variants (Zhang et al. 1999; Waterham and Ebberink 2012; Steinberg et al. 2004).

Clinical sensitivity for del/dup testing is expected to be low, but non-zero. Three PEX6 multi-exon deletions have been reported so far (Ebberink et al. 2010; Grønborg et al. 2011).

This test provides full coverage of all coding exons of the PEX6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.