Dihydropteridine Reductase (DHPR) Deficiency via the QDPR Gene

Hyperphenylalaninemias due to tetrahydrobiopterin (BH4) deficiency are a result of a disruption in phenylalanine homeostasis and dopamine and serotonin biosynthesis. These disorders are caused by pathogenic variants in the genes encoding enzymes involved in the biosynthesis or regeneration of BH4. The phenylalanine, tyrosine, and tryptophan hydroxylases all require BH4 as a cofactor, and lack of this cofactor results in secondary hyperphenylalaninemia and depletion of the neurotransmitters dopamine and serotonin. Early detection and treatment can reduce neurologic symptoms (Blau et al. 2014).

Patients with dihydropteridine reductase (DHPR) deficiency are usually detected via newborn screening due to hyperphenylalaninemia. Urinary pterin profiles and DHPR activity in dry blood spots on Guthrie cards are widely used for the clinical diagnosis of DHPR deficiency (Blau et al. 2014, Trujillano et al. 2014). These patients are unresponsive to a phenylalanine-restricted diet and develop severe neurologic symptoms including psychomotor retardation, delayed development, tonal abnormalities, seizures, and dystonia. Patients may also present with abnormal thermogenesis, microcephaly, swallowing difficulties and hypersalivation. Symptoms will become apparent typically between birth and four months of age (Blau et al. 2014, Trujillano et al. 2014).

Dihydropteridine reductase deficiency is inherited in an autosomal recessive manner. The QDPR gene (chromosome 4p15.3, 7 exons) encodes the DHPR enzyme which is involved in the regeneration of tetrahydrobiopterin from quinonoid dihydropteridine (Smooker and Cotton 1995). Reported pathogenic variants include mostly missense with some nonsense, splicing, and small insertions/deletions (Human Gene Mutation Database). Pathogenic variants are spread evenly along the coding sequence. Some of these variants have been mapped to the NADH binding domain of the protein (Smooker and Cotton 1995). Other inborn errors of BH4 metabolism can present with a similar clinical course and involve 6-pyruvoyl tetrahydropterin synthase (PTS gene), GTP cyclohydrolase I (GCH1 gene), and pterin-4α-carbinalamine dehydratase (PCBD1 gene) (Blau et al. 2014, Trujillano et al. 2014).

Near 100% clinical sensitivity. In a collective total of 30 patients from different families with a clinical diagnosis of dihydropteridine reductase (DHPR) deficiency, all patients were found to be homozygous or compound heterozygous for pathogenic variants (Romstad et al. 2000; Smooker et al. 1999; Dianzani et al. 1998). Analytical sensitivity should also be close to 100% because all reported pathogenic variants thus far are detectable by sequencing.

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