Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.
Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.
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DOI：
10.1016/j.mam.2022.101153
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发表时间：
2023-06
影响因子：
10.6
通讯作者：
Bainbridge, Matthew
中科院分区：
文献类型：
--
作者：
Hopkins, Christopher E.;Brock, Trisha;Caulfield, Thomas R.;Bainbridge, Matthew
精密医学致力于高度个性化的疾病治疗，其理念是每个人独特的基因构成和环境暴露不仅给他们留下了疾病的倾向，也是一种最佳的治疗方法。在罕见疾病领域，遗传倾向往往是驱动疾病表现的主要机制。对于这种主要是单基因疾病的疾病，可能存在一个与表型相关的致病基因。因此，查询患者的基因组是否存在可能导致疾病的致病变异变得重要。确定一种变异是否致病对这些分析至关重要，而且可能具有挑战性，因为许多致病变异都是新的，因此没有可用的功能数据来帮助对它们进行分类。这一问题因需要快速评估致病性而加剧，因为许多遗传性疾病出现在幼儿身上，如果不进行快速诊断和治疗，他们的发病率和死亡率将会增加。在这里，我们讨论动物模型的实用性，主要集中在线虫上，作为组织培养和电子计算机方法的对比，重点是这些系统如何用于确定具有不确定意义的变异的致病性，然后用于筛选新的治疗方法。
Precision medicine strives for highly individualized treatments for disease under the notion that each individual’s unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient’s genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, ergo, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on C. elegans, as a contrast to tissue culture and in silico approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics.
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