In silico analysis and the pathogenicity classification of PTS gene variants among Iranian population

Abstract

Background 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is an autosomal recessive disorder caused by PTS gene mutations. The aim of this study was to collect all PTS gene variants detected among Iranian patients with PTPS deficiency as well as in the Iranome project and classify them based on American College of Medical Genetics and Genomics (ACMG-AMP) guidelines. Results The number of PTS gene variants reported among Iranian PTPS patients and in the Iranome project were 19 and 36, respectively. Given that one variant was reported in both of our sources, the total number of variants was 54. These variants were classified as pathogenic (n = 11), likely pathogenic (n = 7), VUS (n = 23), likely benign (n = 1), and benign (n = 12). Out of 19 variants reported among Iranian PTPS patients, c.155A>G (p.Asn52Ser, rs104894275) and c.317C>T (p.Thr106Met, rs200712908) were the most frequent ones, each with a frequency of 10%. c.84-3C>G (rs1230781262) (7.5%) and c.281A>T (p.Asp94Val) (5%) were in the next ranks of the list of variants. Conclusions The ACMG-AMP criteria need to be updated depending on the type of disease. In addition, to the best of our knowledge, no template has been described for classifying the variants identified in PTPS deficiency. Therefore, this study can be a good reference for future studies in this subject.

Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran

“…Moreover, a study conducted by Khamooshian et al in connection with PTS gene variants in Iran reported this mutation (Khamooshian et al, 2022). This study showed that 59.2% (32 of 54) of the mutations found in the PTS gene in the Iranian race were found in the intronic region.…”

“…Therefore, when examining mutations in this gene, attention should be paid to the intronic regions as well. In Khamooshian et al's study, it was shown that this mutation has a deleterious effect on seven or more tools for predicting the effect of mutations (Khamooshian et al, 2022).…”