Genetic Screening of ATP7B Gene in Iranian Wilson Disease Patients: A diverse landscape of pathogenic variants

Background/Objective: Wilson's disease (WD) is an autosomal recessive condition caused by mutations in the ATP7B gene, leading to the copper accumulation in various organs. Data on the ATP7B mutation spectrum in Iran and the Middle East is insufficient. This study aims to screen the ATP7B gene in unrelated Iranian families (n = 23) from northeastern Iran. Methods DNA was extracted from peripheral blood, and variant screening was performed using direct sequencing of the entire ATP7B gene coding region. The full 3D structure of the defective proteins was determined using the I-TASSER software. Results The overall frequency of causative variant detection was 84.7% (39/46). Among the 23 patients with WD, we identified 13 different causative variants: eight missense, two nonsense, one splicing, one deletion, and one deletion/insertion changes. Two of which were novel: c.3431delTinsAGA (p.Phe1144Ter) and c.1156G > A (p.Gly386Arg). The c.2807T > A (p.Leu936Ter) variant at exon 12 was the most prevalent in our study, with an allelic frequency of 17.39%, followed by c.3188C > T (p.Ala1063Val) at exon 14, exhibiting an allelic frequency of 13.04%. Exons 12, 13, and 14 were identified as mutation hot spots, with detection rate of 50% (23/46). Ten out of the 13 variants identified in our study were reported for the first time in Iran (this report). Conclusion We reported two novel variants that broaden the known spectrum of mutations associated with the ATP7B gene. The variants identified in this study can facilitate carrier screening and presymptomatic detection and can be used in prenatal genetic diagnosis in affected families.