Hydroxyprolinemia via the PRODH2 Gene

Hydroxyprolinemia is an inborn error of amino acid metabolism that is caused by deficient hydroxyproline degradation. Thus far, no clinical phenotype has been associated with hydroxyprolinemia, and it is therefore considered most likely to be a benign biochemical disorder. However, it is difficult to differentiate between hydroxyproline and leucine, isoleucine and alloisoleucine via tandem mass spectrometry (MS/MS), a common technique used for newborn screening (NBS). As elevated levels of leucine, isoleucine and alloisoleucine are suggestive of maple syrup urine disease (MSUD), it is possible that individuals with hydroxyprolinemia may have a false positive NBS result suggestive of MSUD. For patients with positive NBS results for MSUD yet no positive molecular diagnosis, molecular testing for hydroxyprolinemia may be helpful (Staufner et al. 2016. PubMed ID: 27139199).

Hydroxyprolinemia is a rare autosomal recessive inborn error of metabolism caused by pathogenic sequence variants in the PRODH2 gene, which is located on chromosome 19 at 19q13.12. In the only molecular study of PRODH2 performed to date, molecularly confirmed hydroxyprolinemia was reported to be at least 2.5 times more prevalent than MSUD (estimates of ~1/23,000 to 1/47,000 for hydroxyprolinemia compared to ~1/121,000 for MSUD) (Staufner et al. 2016. PubMed ID: 27139199). Reported causative variants in PRODH2 are mainly missense, although in-frame deletions, nonsense and frameshift variants have also been identified (Staufner et al. 2016. PubMed ID: 27139199).

The PRODH2 gene encodes the enzyme proline dehydrogenase, which is responsible for the first step of hydroxyproline breakdown. Hydroxyproline is a major component of collagen. Based on recent insights into the mechanism of this enzyme, it has been suggested that the gene name be changed to HYPDH (hydroxyproline dehydrogenase) (Staufner et al. 2016. PubMed ID: 27139199).

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 (Staufner et al. 2016. PubMed ID: 27139199).

This test provides full coverage of all coding exons of the PRODH2 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).