背景:威尔逊病(WD)是一种罕见的常染色体隐性遗传的铜代谢障碍,是由于铜转运蛋白ATP7B的突变引起的。在ATP7B突变的患者中,临床表现通常存在惊人的变异性。包括兄弟姐妹。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而引起的,铜代谢基因的遗传变异是该疾病的修饰位点。
目的:阐明两个WD家族的两个兄弟姐妹之间惊人的临床异质性的遗传基础。
方法:疾病诊断和随后的临床检查由临床专家进行。两个家庭中的年轻兄弟姐妹都比年长的兄弟姐妹在年轻时表现出早期的神经系统表现。有趣的是,据报道,只有年轻的兄弟姐妹有肝脏表现。对所有四个个体进行外显子组测序以了解他们的异质性表型结果。
结果:遗传筛查显示每个家族的兄弟姐妹之间的ATP7B变异谱没有差异。然而,发现这两个家族的兄弟姐妹在与铜代谢和/或其他神经和肝脏疾病有重叠症状的怀疑修饰基因中含有相互排斥的致病变异,viz.,CFTR,PPARG,ABCB11,ATP7A,CYP2D6,mTOR,TOR1A,CP,这可能解释了它们不同的临床表型。
结论:具有相同ATP7B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。
BACKGROUND: 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 ATP7B 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.
OBJECTIVE: To elucidate the genetic basis of striking clinical heterogeneity among two siblings of two families with WD.
METHODS: 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.
RESULTS: Genetic screening revealed no difference in the ATP7B 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., CFTR, PPARG, ABCB11, ATP7A, CYP2D6, mTOR, TOR1A, and CP, which can potentially explain their differential clinical phenotypes.
CONCLUSIONS: Clinical heterogeneity between siblings with WD with the same ATP7B mutation profile may be attributed to the presence of different pathogenic variants in potential modifier genes.