Primary Hyperoxaluria Panel

Primary hyperoxaluria (PH) is an autosomal recessive disorder of endogenous glyoxylate metabolism characterized by an accumulated urinary excretion of calcium oxalate (Rumsby 2008; Coulter-Mackie et al. 2002; Milliner et al. 2015). The increased oxalate excretion causes nephrolithiasis, nephrocalcinosis and renal failure followed by systemic oxalate deposition. The age at onset of PH ranges from the first year of life to adulthood with varied disease severity. AGXT-causative type 1 PH is the most severe form, accounting for up to 80% of genetically characterized PH patients (Hopp et al. 2015). GRHPR-causative type 2 PH is less severe than type 1, accounting for about 10% of genetically characterized PH patients. HOGA1-causative type 3 PH is the least severe, accounting for the remaining about 10% of genetically characterized PH patients.

Primary hyperoxaluria is an autosomal recessive disorder, which comprises three types depending on the causative genes: type 1 (AGXT), type 2 (GRHPR) and type 3 (HOGA1) (Hopp et al. 2015).

AGXT has 11 coding exons that encode the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. Genetic defects of AGXT throughout the whole coding region include missense, nonsense, splicing site pathogenic variants, and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving AGXT have also been reported, but are relatively uncommon.

GRHPR has 9 coding exons that encode the glyoxylate reductase/hydroxypyruvate reductase, which catalyzes the reduction of hydroxypyruvate to D-glycerate, the reduction of glyoxylate to glycolate and the oxidation of D-glycerate to hydroxypyruvate. Genetic defects of GRHPR throughout the whole coding region include missense, nonsense, splicing site pathogenic variants and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions and duplications involving GRHPR have not been reported.

HOGA1 (formerly DHDPSL) has 7 coding exons that encode the 4-hydroxy-2-oxoglutarate aldolase, which catalyzes the final step in the metabolic pathway of hydroxyproline. Genetic defects of HOGA1 throughout the whole coding region include missense, nonsense, splicing site pathogenic variants and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions and duplications involving HOGA1 have not been reported.

In a sequencing study of 301 PH families (355 patients), defects in the AGXT, GRHPR and HOGA1 genes were found in 68.4%, 9.3% and 11% of these families, respectively (Hopp et al. 2015). The remaining 11.3% had no pathogenic variants found in these three genes.

Large deletions and/or duplications have not been documented in GRHPR or HOGA1 in Human Gene Mutation Database (HGMD) while large deletions involving AGXT have been reported, but are relatively uncommon.

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.