Variation spectrum and reevaluation of selected VUS of ATP7B in a Chinese Wilson disease cohort

Aim: The clinical diagnosis of Wilson disease (WD) remains challenging due to ethnic and phenotypic heterogeneity, as well as the high prevalence of variants of unknown significance (VUS). This study aimed to update the genetic variation spectrum in the Chinese population and reevaluate a subset of VUS to improve the accuracy of genetic diagnosis.

Methods: Patients suspected of having WD and known non-WD controls were selected and underwent ATP7B-targeted sequencing. The variant spectrum was analyzed. Recurrent VUS, particularly those associated with very low ceruloplasmin levels, were further evaluated based on their mutational characteristics, including pathogenic variant linkage disequilibrium and zygosity.

Results: We analyzed a total of 679 WD suspects and 251 controls. Of these, 292 patients (282 cases) carried disease-causing variants or VUS. Demographic characteristics were comparable between groups. The most recurrent pathogenic variants - p.Arg778Leu, p.Pro992Leu, and p.Ala874Val - differed significantly from those observed in the Caucasian population. Among the 79 detected VUS, 26 were novel. The most frequent VUS included p.Leu770=, p.Val1297Ile, p.Val1106Ile, p.Ile929Val, p.Ala1003=, p.Ala476Thr, and p.Asp196Glu. Following reevaluation of 9 VUS, we classified p.Val1106Ile, the splice site variant c.1543+40G>A, p.Ala1018Val, p.Leu1088Ser, p.Gly1335Arg, and the synonymous variants p.Ile1338= and p.Ala1003= as pathogenic candidates. Notably, p.Val1106Ile frequently co-occurred with pathogenic mutations, while p.Leu770= was reclassified as a tag-only variant.

Conclusion: Our study reveals a distinct mutation spectrum in the Chinese population, providing evidence for the classification of VUS. The unique mutational patterns observed at specific loci suggest their potential structural significance within the ATP7B protein.