Khdair Ahmad Fareed, Aburizeg Dunia, Rayyan Yaser, Tamimi Tarek A, Burayzat Salma, Ghanma Abdullah, Barbar Maha, Azab Bilal
Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, School of Medicine, The University of Jordan, Amman, Jordan.
Jordan University Hospital, Amman, Jordan.
J Pediatr Gastroenterol Nutr. 2025 Mar;80(3):471-481. doi: 10.1002/jpn3.12446. Epub 2025 Jan 6.
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.
Twenty-four Jordanian families with WD underwent clinical evaluation and genetic profiling by whole-exome and Sanger sequencing.
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.
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.
威尔逊病（WD）是一种常染色体隐性疾病，会破坏铜稳态。ATP酶铜转运β（ATP7B）基因被认为是WD的致病基因。与WD相关的常见症状包括肝脏、神经、精神和眼部表现。WD的基因情况在中东地区研究不足，在约旦从未被研究过。我们旨在调查几个有一名或多名WD患者的不相关约旦家庭的基因特征。
24个患有WD的约旦家庭接受了临床评估，并通过全外显子组测序和桑格测序进行基因分析。
令人惊讶的是，在8个无血缘关系的近亲家庭中首次仅在纯合状态下鉴定出相同的变异（ATP7B:c.3551C>T;p.Ile1184Thr）。在我们的研究之前，该变异的先前分类要么是意义未明变异（VUS），要么是可能致病（LP）。有趣的是，携带该变异的患者在家族内和家族间水平上均表现出不同的临床表现，正如先前WD病例中所描述的那样。在招募的个体中，诊断年龄、肝脏表现、神经精神受累情况以及凯泽-弗莱舍环的出现情况在存在和严重程度方面差异显著。经过我们的调查，基于临床数据和共分离分析，我们首次将变异ATP7B:c.3551C>T;p.Ile1184Thr从VUS/LP重新分类为致病。此外，我们的基因分析通过确立或排除WD诊断，有助于解决诊断上的模糊性。
由于在多个无血缘关系的家庭中发现了已鉴定的变异（ATP7B:p.Ile1184Thr），我们为在约旦人群中将该变异潜在地视为复发性或可能的奠基者变异创造了一条途径。我们的工作首次揭示了约旦WD的分子基础，并汇总了中东地区导致WD的变异。最终，我们工作的结果可以指导设计约旦地区特定的WD靶向基因检测，并为非典型WD表现的临床决策提供有价值的见解。
