Xanthinuria Type I via the XDH Gene

Xanthinuria is characterized by the accumulation of xanthine in serum and urine (Dent and Philpot, 1954. PubMed ID: 13118765; Raivio et al., 2014). Patients also present with hypouricaemia and hypouricosuria due to insufficient breakdown of xanthine (Raivio et al., 2014). Affected individuals may develop urinary xanthine calculi leading to hematuria, crystalluria, and renal colic (Bradbury et al., 1995. PubMed ID: 7577413; Carpenter et al., 1986. PubMed ID: 3755469). Clinical variability is observed and only ~50% of patients develop urolithiasis. Xanthinuria type I occasionally presents with muscle pains and cramps due to xanthine deposition (Chalmers et al., 1969. PubMed ID: 4902314; Parker et al., 1970. PubMed ID: 5414104). 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.

Xanthinuria Type I is a rare autosomal recessive disorder caused by pathogenic variants in the XDH gene located on chromosome 2p23.1. The XDH gene encodes xanthine dehydrogenase (1333 amino acids, MW 146 kDa) which is functional as a homodimer. The xanthine dehydrogenase enzyme catalyzes two independent steps in purine metabolism: the oxidation of hypoxanthine to xanthine and xanthine to uric acid. The N-terminal 20-kDA domain contains two non-identical Fe-S clusters, the middle 40-kDa contains an FAD center, and the C-terminal 85-kDa domain binds molybdenum cofactor. Pathogenic variants include missense, nonsense, and small frameshift deletions or insertions (Arikyants et al., 2006. PubMed ID: 17115198; Eggermann et al., 2013. PubMed ID: 23249873; Ichida et al., 1997. PubMed ID: 9153281; Levartovsky et al., 2000. PubMed ID: 10844591; Nakamura et al., 2012. PubMed ID: 22981351; Sakamoto et al., 2001. PubMed ID: 11379872; Stiburkova et al., 2012. PubMed ID: 21963464; Human Gene Mutation Database). Incidence estimates 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). 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).

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.

Clinical sensitivity for Copy Number Variants will likely be low since only one gross deletion has been reported to date (Eggermann et al., 2013. PubMed ID: 23249873).

This test provides full coverage of all coding exons of the XDH 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).