Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism caused due to mutations in the copper transporter ATP7B. There is often a striking variability of clinical manifestations among patients with mutations, including in siblings. This phenomenon may be caused by individual differences in copper accumulation in hepatocytes and intolerance to copper toxicity as governed by genetic variations in copper metabolism genes acting as modifier loci to the disease. To elucidate the genetic basis of striking clinical heterogeneity among two siblings of two families with WD. The disease diagnosis and subsequent clinical examinations were performed by expert clinicians. The younger siblings in both families presented with early neurological manifestations at a younger age than their older siblings. Interestingly, only the younger siblings were reported to have had hepatic manifestations. Exome sequencing of all the four individuals was performed to understand their heterogeneous phenotypic outcomes. Genetic screening revealed no difference in the variant spectrum between the siblings of each family. However, the siblings of both the families were found to harbor mutually exclusive pathogenic variants in suspected modifier genes implicated in copper metabolism and/or other neurological and hepatic disorders having overlapping symptoms with WD, viz., and which can potentially explain their differential clinical phenotypes. Clinical heterogeneity between siblings with WD with the same mutation profile may be attributed to the presence of different pathogenic variants in potential modifier genes.

中文翻译：

---

努力鉴定患有威尔逊病的兄弟姐妹中表现出显着临床异质性的遗传决定因素：对两个印度家庭的外显子组分析研究

威尔逊病 (WD) 是一种罕见的常染色体隐性铜代谢疾病，由铜转运蛋白 ATP7B 突变引起。携带突变的患者（包括兄弟姐妹）的临床表现通常存在显着差异。这种现象可能是由于肝细胞中铜积累的个体差异以及对铜毒性的不耐受引起的，铜毒性是由作为疾病修饰基因座的铜代谢基因的遗传变异控制的。旨在阐明两个 WD 家庭的两个兄弟姐妹之间显着临床异质性的遗传基础。疾病诊断和随后的临床检查由临床专家进行。两个家庭中的弟弟妹妹比哥哥姐姐更早出现早期神经系统症状。有趣的是，据报道只有弟弟妹妹有肝脏表现。对所有四个人进行外显子组测序，以了解他们的异质表型结果。基因筛查显示每个家庭的兄弟姐妹之间的变异谱没有差异。然而，两个家庭的兄弟姐妹被发现在与铜代谢和/或其他与 WD 有重叠症状的神经和肝脏疾病有关的可疑修饰基因中存在相互排斥的致病变异，这可能解释他们不同的临床表型。具有相同突变谱的 WD 兄弟姐妹之间的临床异质性可能归因于潜在修饰基因中存在不同的致病变异。