Submission Details

The relationship between PTS and Biopterin-deficient hyperphenylalaninemia a, an autosomal recessive disorder of biopterin synthesis, was evaluated using the ClinGen Clinical Validity Framework as of December 22nd, 2017. PTS encodes 6-pyruvoyl-tetrahydropterin synthase (PTPS), which catalyzes the second step of biopterin synthesis. Hundreds of patients with deficiency of PTPS activity have been reported (Opladen et al, 2012, PMID 22729819). Variants in PTS were first reported in humans with this disease as early as 1994 (Thöny et al, PMID 8178819). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen unique variants (missense, frameshift, splice site, inframe deletion, and intronic variants resulting in pseudoexon inclusion) have been reported in humans. Variants in this gene were curated in 9 probands in 5 publications (Thöny et al, 1994; PMID 8178819; Oppliger et al, 1997, PMID 9222757; Meili et al, 2007, PMID 19280650; Leuzzi et al, 2010, PMID 20059486; Brasil et al, 2011, PMID 21542064). More evidence is available in the literature but the maximum score for genetic evidence (12 points ) has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the function of PTPS, which is consistent with the disease process (Takikawa et al, 1986, PMID 3511907; Longo 2009, PMID 19234759), as well as the biochemical features of a null mouse model (Sumi-Ichinose et al, 2001, PMID 11517215). In summary, PTPS is definitively associated with Biopterin-deficient hyperphenylalaninemia a. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on December 22nd, 2017.