Rare diseases occur in a smaller proportion of the general population, which is variedly defined as less than 200 000 individuals (US) or in less than 1 in 2000 individuals (Europe). Although rare, they collectively make up to approximately 7000 different disorders, with majority having a genetic origin, and affect roughly 300 million people globally. Most of the patients and their families undergo a long and frustrating diagnostic odyssey. However, advances in the field of genomics have started to facilitate the process of diagnosis, though it is hindered by the difficulty in genome data analysis and interpretation. A major impediment in diagnosis is in the understanding of the diverse approaches, tools and datasets available for variant prioritization, the most important step in the analysis of millions of variants to select a few potential variants. Here we present a review of the latest methodological developments and spectrum of tools available for rare disease genetic variant discovery and recommend appropriate data interpretation methods for variant prioritization. We have categorized the resources based on various steps of the variant interpretation workflow, starting from data processing, variant calling, annotation, filtration and finally prioritization, with a special emphasis on the last two steps. The methods discussed here pertain to elucidating the genetic basis of disease in individual patient cases via trio- or family-based analysis of the genome data. We advocate the use of a combination of tools and datasets and to follow multiple iterative approaches to elucidate the potential causative variant.

中文翻译：

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用于罕见病基因发现的基因组测序数据分析

罕见疾病发生在总人口中的一小部分，其不同的定义是少于 200 000 人（美国）或少于 2000 人中的 1 人（欧洲）。虽然罕见，但它们共同构成了大约 7000 种不同的疾病，其中大多数具有遗传起源，并影响全球大约 3 亿人。大多数患者及其家人都经历了漫长而令人沮丧的诊断之旅。然而，基因组学领域的进步已经开始促进诊断过程，尽管它受到基因组数据分析和解释困难的阻碍。诊断中的一个主要障碍是了解可用于变体优先级排序的各种方法、工具和数据集，分析数百万个变体以选择一些潜在变体的最重要步骤。在这里，我们回顾了可用于罕见病遗传变异发现的最新方法学发展和工具范围，并推荐了用于变异优先级的适当数据解释方法。我们根据变异解释工作流程的各个步骤对资​​源进行了分类，从数据处理、变异调用、注释、过滤和最后的优先级开始，特别强调最后两个步骤。这里讨论的方法涉及通过对基因组数据进行基于三人组或家庭的分析来阐明个体患者病例中疾病的遗传基础。