Wilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B. A streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones. Based on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients’ management and in particular on therapy.

中文翻译：

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威尔逊病的基因型-表型变量相关性：具有相似基因型的两个姐妹的临床病史。

威尔逊病（WD）是一种常染色体隐性遗传疾病，归因于13q14.3号染色体上ATP7B基因的突变。蛋白质功能不足会导致铜蓝蛋白血液水平降低，并在肝脏，基底神经节和脉络膜中积累铜。主要临床表现为高转氨血症，震颤，构音障碍，肌张力障碍和精神病症状。WD的表型变异性很大，其发作可能是异质性的：儿童时期最常见的类型是肝脏受累，其次是神经疾病。基因型-表型相关性的存在尚未得到充分证明。表型变异性可以通过在突变ATP7B存在下调节铜代谢的其他修饰基因的干预来解释。在两个携带相同ATB7B基因型的西西里姐妹中观察到了明显的表型变异性[c.3207C> A / c.3904-2A> G]。尽管两者均在10岁时开始出现体征，但首先以神经系统体征为特征（震颤，运动不协调，语言和认知障碍），而肝脏受累则是唯一的体征。他们开始了相同的螯合疗法。经过20年的随访，前者受到严重影响（MRI显示基底神经节铜沉积物和高胆固醇血症的肝，血小板减少症），而后者仅表现为中等程度的肝脏肿大。在文献中，埃及人群中也发现了剪接突变c.3904-2A> G，与急性肝衰竭或慢性肝病有关，可能是地中海地区的典型情况，没有在其他地理区域报告。根据我们在西西里岛东部的临床经验，即使存在相同的基因型，WD仍有相当大的表型变异性。突变c.3904-2A> G可能与地中海人口的这种表型变异有关，但应进行进一步的研究。这种情况可以通过在有缺陷的ATP7B蛋白功能存在下调节铜代谢的修饰基因的干预来解释。下一代测序或全外显子组分析对其作用的进一步研究可能会对患者的治疗，尤其是治疗产生深远影响。即使存在相同的基因型 突变c.3904-2A> G可能与地中海人口的这种表型变异有关，但应进行进一步的研究。这种情况可以通过在有缺陷的ATP7B蛋白功能存在下调节铜代谢的修饰基因的干预来解释。下一代测序或全外显子组分析对其作用的进一步研究可能会对患者的治疗，尤其是治疗产生深远影响。即使存在相同的基因型 突变c.3904-2A> G可能与地中海人口的这种表型变异有关，但应进行进一步的研究。这种情况可以通过在有缺陷的ATP7B蛋白功能存在下调节铜代谢的修饰基因的干预来解释。通过下一代测序或全外显子组分析对其作用的进一步研究可能对患者的治疗，尤其是治疗产生深远的影响。