Genetic screening of ATP7B gene in Iranian Wilson disease patients: a diverse landscape of pathogenic variants

Abstract Background 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 are insufficient. This study aims to screen the ATP7B gene in unrelated Iranian families (n = 22) 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 predicted using the I-TASSER software. Results The overall frequency of causative variant detection was 84.09% (37/44). Among the 22 patients with WD, we identified 12 distinct causative variants: seven missense, two nonsense, one splicing, one deletion, and one deletion/insertion changes. Nine of these variants were reported for the first time in Iran. One of the identified variants was novel, c.3431delTinsAGA (p.Phe1144Ter), and had not been previously reported worldwide. The c.2807T > A (p.Leu936Ter) variant in exon 12 was the most prevalent in our study, with an allelic frequency of 18.18%, followed by c.3188C > T (p.Ala1063Val) at exon 14, exhibiting an allelic frequency of 13.63%. Exons 12, 13, and 14 were identified as mutation hotspots, with detection rate of 52.27% (23/44). Conclusion We reported one novel variant 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.