Xanthinuria Type II via the MOCOS Gene

Xanthinuria type II is an inherited metabolic disorder characterized by the deficiency of both of the molybdenum-cofactor requiring enzymes xanthine dehydrogenase and aldehyde oxidase (Mendel, 2009. PubMed ID: 19623604; Raivio et al., 2014). Biochemically, patients have greatly elevated serum and urinary xanthine, elevated serum and urinary hypoxanthine, and hypouricemia. The majority of patients may be asymptomatic, although roughly one-third of patients may present with urinary tract xanthine calculi that may lead to hematuria, crystalluria, renal colic or acute renal failure. Myositis is also sometimes observed (Raivio et al., 2014; Ceballos-Picot and Jinnah, 2016). Xanthinuria Type II is characterized by deficiency in xanthine dehydrogenase and aldehyde oxidase due to pathogenic variants in the molybdenum cofactor sulfurase, MOCOS, gene. Although the two types have similar clinical presentation, a distinction between the two types is based on the ability to oxidize allopurinol to oxypurinol (Raivio et al., 2014).

Xanthinuria Type II is a rare autosomal recessive disorder caused by pathogenic variants in the MOCOS gene located on chromosome 18 at 18q12.2. Although clinical reports indicate that types I and II are roughly equal in incidence, only a handful of type II patients have been molecularly diagnosed (Raivio et al., 2014). Reported pathogenic variants in MOCOS include missense, nonsense, and small frameshifts (Ichida et al., 2001. PubMed ID: 11302742; Yamamoto et al., 2003. PubMed ID: 14624414; Peretz et al., 2007. PubMed ID: 17368066; Zhou et al., 2015. PubMed ID: 25967871). Incidence estimates for xanthinuria types I and II range from 1 in 6,000 to 1 in 69,000 (Harkness et al., 1983. PubMed ID: 6422142; Harkness et al., 1986. PubMed ID: 3104682; Raivio et al., 2014). This large range may reflect the rarity of the disease and population differences. Xanthinuria may be more prevalent in Mediterranean countries (Raivio et al., 2014).

The MOCOS gene encodes molybdenum cofactor sulfurase, which is required for resulfuration of the molybdenum synthase enzyme during biosynthesis of the molybdenum cofactor molybdopterin (Johnson and Duran, 2014).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because the great majority of pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the MOCOS 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).