Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) Syndrome via the VPS33B Gene

Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARC syndrome; OMIM #208085) is a multisystem disorder with features of arthrogryposis multiplex congenita, renal tubular hypoplasia, and cholestatic liver disease (Di Rocco et al. Am J Med Genet 37:237-240, 1990; Di Rocco et al. Eur J Pediatr 154:835-839, 1995). Life-threatening complications of malabsorption secondary to cholestatic jaundice appear shortly after birth (Nezelof et al. J Pediatrics 94:258-260, 1979). The majority of patients succumb in several weeks to several months of life (Gissen et al. Hum Genet 120:396-409, 2006). Renal disease involves renal tubular cell degeneration and nephrocalcinosis (Saraiva et al. J Pediatrics 117:761-763, 1990). Liver histology in ARC syndrome has been reviewed (Horslen et el. J Med Genet 31:62-64, 1994). Bile duct hypoplasia and low gamma glutamyl transpeptidase activity are documented (Gissen et al. 2006). Other clinical findings described in a cohort of 62 ARC syndrome patients included failure to thrive (100%) and structural cardiac defects (10%) (Gissen et al. 2006). The same study found a high rate of life-threatening hemorrhagic events during diagnostic organ biopsy procedures. Severe osteopenia with congenital fractures has been reported in one ARC syndrome patient (Taha et al. Am J Med Genet 143A:2835-2837, 2007).

ARC syndrome is inherited as an autosomal recessive disorder. VPS33B (OMIM #608552) was found to be a causative gene for ARC syndrome (Gissen et al. Nat Genet 36:400-404, 2004), and is thought to account for approximately 75% of cases (Cullinane et al. 2010). Nonsense and splice site variants represent the most common forms of VPS33B variant although missense and frame-shifting variants are also reported. Variants in the VIPAR gene, which encodes a ‘VPS33B-interacting protein,’ have been found in all cases of classic ARC syndrome when VPS33B variants were not identified (Cullinane et al. Nature Genet 42:303-312, 2010).

Analytical sensitivity should be high because all variants reported to date are detectable by direct sequence analysis of genomic DNA. Clinical sensitivity appears to be high also. Twenty-eight of 35 ARC syndrome families in one study were found to have two VPS33B variants (Gissen et al. 2006).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the VPS33B gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.