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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.

Abstract Background Familial Mediterranean fever (FMF), known as a disease with a high prevalence rate among Armenian, Turkish, Jewish, and Arab descent populations, occurs as a result of pathogenic variants in mediterranean fever (MEFV) gene. The aim of this study was to review the spectrum and frequency of MEFV gene mutations reported among Iranian FMF patients. Methods After performing a systematic review of the literature and implementation of inclusion and exclusion criteria, 16 articles published between 2004 and 2020, involving 4,256 Iranian FMF patients, were included. Results A total of 38 different MEFV gene mutations were identified. The most common mutations among Iranian FMF patients were: p.M694V (c.2080A > G) (20.27%), p.E148Q (c.442G > C) (10.27%), p.V726A (c.2177T > C) (8.24%), p.M680I (both c.2040G > C and c.2040G > A) (7.20%), p.R761H (c.2282G > A) (2.1%), and p.M694I (c.2082G > A) (2. 1%). The frequencies of these mutations were significantly different in different parts of the country. Conclusions The ranks and frequencies of p.M694V, p.E148Q, p.V726A, p.M680I, and p.M694I in our population were closer to those observed in the Mediterranean countries, especially in the Middle Eastern Arab populations. Although some comprehensive studies have been performed on Azeri Turkish patients living in northwestern Iran, studies in other areas, especially in eastern Iran, have been very limited. One reason for this observation could be due to the low frequency of FMF patients in those areas. Regardless of the reason for this, the exact spectrum and frequency of MEFV gene mutations in Iranian FMF patients remain unclear. Therefore, comprehensive future studies in different parts of the country are recommended.

Abstract Background The quantification of hemoglobin A2 (Hb A2; α2δ2) is used as a valuable test to differentiate α- and ß-thal carriers in clinical laboratories. Therefore, the HBD (δ-globin) gene variants could result in reduced levels of Hb A2 and have implications for thalassemia screening programs. The aim of the present study was to predict the consequences of HBD gene variants identified in the Iranome project. Results The highest number of variants was in the Persian Gulf Islanders. The variants of p.Gln132Glu (HBD: c.394C>G), p.Gly17Arg (HBD: c.49G>C), p.Thr5Ile (HBD: c.14C>T), and p.Ala28Ser (HBD: c.82G>T) presented damage results in three or more prediction tools. In addition, it seems that the p.Gly30= (HBD: c.90C>T) decreases the use of authentic splice and, instead, creates a new donor splice site (DSS) or leads to the use of a cryptic DSS. Conclusions Most of these variants have been associated with a decrease in Hb A2 levels. Due to the high mutational diversity in the HBB gene in the Iranian population and the use of Hb A2 quantification to differentiate α- and ß-thal carriers among Iranian clinical laboratories, some attention should be taken to a possible co-inheritance of HBD gene variants to avoid the misdiagnosis of ß-thal carriers.