Genetic profiling of Wilson disease reveals a potential recurrent pathogenic variant of ATP7B in the Jordanian population

Objectives: Wilson disease (WD) is an autosomal-recessive disorder that disrupts copper homeostasis. ATPase copper transporting beta (ATP7B) gene is implicated as the disease-causing gene in WD. The common symptoms associated with WD include hepatic, neurological, psychiatric, and ophthalmic manifestations. The genetic landscape of WD is under-investigated in the Middle East and has never been studied in Jordan. We aimed to investigate the genetic profile of several unrelated Jordanian families with one or more patients affected by WD.

Methods: Twenty-four Jordanian families with WD underwent clinical evaluation and genetic profiling by whole-exome and Sanger sequencing.

Results: Surprisingly, the same variant (ATP7B:c.3551C>T;p.Ile1184Thr) was identified, for the first time, exclusively in the homozygous state, in eight consanguineous unrelated families. Before our study, the previous classification of this variant was either of uncertain significance (VUS) or likely pathogenic (LP). Interestingly, the patients harboring this variant displayed variable clinical manifestations on both the intra- and interfamilial levels, as previously described in cases with WD. The age of diagnosis, hepatic manifestations, neuropsychiatric involvements, and Kayser-Fleischer ring occurrence varied significantly in terms of existence and severity among the recruited individuals. Following our investigation, based on clinical data and co-segregation analysis, we re-classified the variant ATP7B:c.3551C>T;p.Ile1184Thr from VUS/LP to pathogenic, for the first time. Besides, our genetic analysis helped in resolving diagnostic ambiguity by either establishing or ruling out the diagnosis of WD.

Conclusion: Since the identified variant (ATP7B:p.Ile1184Thr) was discovered in multiple unrelated families, we create an avenue for the potential consideration of this variant as a recurrent, or possibly a founder variant, in the Jordanian population. Our work sheds light, for the first time, on the molecular underpinnings of WD in Jordan and compiles the WD-causing variants in the Middle East. Ultimately, the findings of our work can guide designing region-specific targeted genetic testing of WD in Jordan and provide valuable insights to direct clinical decisions for atypical WD presentations.