Background Hereditary hemochromatosis (HH) is a genetic disease, leading to iron accumulation and possible organ damage. Patients are usually homozygous for p. Cys282Tyr in the homeostatic iron regulator gene but may have mutations in other genes involved in the regulation of iron. Next-generation sequencing is increasingly being utilized for the diagnosis of patients, leading to the discovery of novel genetic variants. The clinical significance of these variants is often unknown. Content Determining the pathogenicity of such variants of unknown significance is important for diagnostics and genetic counseling. Predictions can be made using in silico computational tools and population data, but additional evidence is required for a conclusive pathogenicity classification. Genetic disease models, such as in vitro models using cellular overexpression, induced pluripotent stem cells or organoids, and in vivo models using mice or zebrafish all have their own challenges and opportunities when used to model HH and other iron disorders. Recent developments in gene-editing technologies are transforming the field of genetic disease modeling. Summary In summary, this review addresses methods and developments regarding the discovery and classification of genetic variants, from in silico tools to in vitro and in vivo models, and presents them in the context of HH. It also explores recent gene-editing developments and how they can be applied to the discussed models of genetic disease.

中文翻译：

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遗传性血色素沉着症的遗传诊断：发现和理解变异的生物学相关性

背景遗传性血色素沉着症（HH）是一种遗传性疾病，会导致铁积累和可能的器官损伤。患者通常是 p 的纯合子。Cys282Tyr 在稳态铁调节基因中，但可能在参与铁调节的其他基因中发生突变。下一代测序越来越多地用于诊断患者，从而发现了新的遗传变异。这些变异的临床意义通常是未知的。内容 确定这些意义不明的变异的致病性对于诊断和遗传咨询很重要。可以使用计算机计算工具和人口数据进行预测，但需要额外的证据来确定致病性分类。遗传疾病模型，例如使用细胞过表达的体外模型，诱导多能干细胞或类器官，以及使用小鼠或斑马鱼的体内模型在用于模拟 HH 和其他铁疾病时都有自己的挑战和机遇。基因编辑技术的最新发展正在改变遗传疾病建模领域。总结 总之，这篇综述讨论了关于遗传变异的发现和分类的方法和发展，从计算机工具到体外和体内模型，并在 HH 的背景下介绍它们。它还探讨了最近的基因编辑发展以及如何将它们应用于所讨论的遗传疾病模型。基因编辑技术的最新发展正在改变遗传疾病建模领域。总结 总之，这篇综述讨论了关于遗传变异的发现和分类的方法和发展，从计算机工具到体外和体内模型，并在 HH 的背景下介绍它们。它还探讨了最近的基因编辑发展以及如何将它们应用于所讨论的遗传疾病模型。基因编辑技术的最新发展正在改变遗传疾病建模领域。总结 总之，这篇综述讨论了关于遗传变异的发现和分类的方法和发展，从计算机工具到体外和体内模型，并在 HH 的背景下介绍它们。它还探讨了最近的基因编辑发展以及如何将它们应用于所讨论的遗传疾病模型。