Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
Int J Mol Sci. 2018 May 27;19(6):1584. doi: 10.3390/ijms19061584.
The biggest challenge geneticists face when applying next-generation sequencing technology to the diagnosis of rare diseases is determining which rare variants, from the dozens or hundreds detected, are potentially implicated in the patient's phenotype. Thus, variant prioritization is an essential step in the process of rare disease diagnosis. In addition to conducting the usual in-silico analyses to predict variant pathogenicity (based on nucleotide/amino-acid conservation and the differences between the physicochemical features of the amino-acid change), three important concepts should be borne in mind. The first is the "mutation tolerance" of the genes in which variants are located. This describes the susceptibility of a given gene to any functional mutation and depends on the strength of purifying selection acting against it. The second is the "mutational architecture" of each gene. This describes the type and location of mutations previously identified in the gene, and their association with different phenotypes or degrees of severity. The third is the mode of inheritance (inherited vs. de novo) of the variants detected. Here, we discuss the importance of each of these concepts for variant prioritization in the diagnosis of rare diseases. Using real data, we show how genes, rather than variants, can be prioritized by calculating a gene-specific mutation tolerance score. We also illustrate the influence of mutational architecture on variant prioritization using five paradigmatic examples. Finally, we discuss the importance of familial variant analysis as final step in variant prioritization.
当遗传学家将下一代测序技术应用于罕见病的诊断时，面临的最大挑战是确定在数十或数百种检测到的罕见变体中，哪些变体可能与患者的表型有关。因此，变体优先级排序是罕见病诊断过程中的一个重要步骤。除了进行常规的计算机分析以预测变体的致病性（基于核苷酸/氨基酸的保守性以及氨基酸变化的物理化学特征之间的差异）外，还应牢记三个重要概念。第一个概念是变体所在基因的“突变容忍度”。这描述了给定基因对任何功能突变的敏感性，并且取决于针对该基因的纯化选择的强度。第二个概念是每个基因的“突变结构”。这描述了先前在该基因中鉴定出的突变的类型和位置，以及它们与不同表型或严重程度的关联。第三个概念是检测到的变体的遗传模式（遗传或新生）。在这里，我们讨论了这些概念对于罕见病诊断中变体优先级排序的重要性。使用真实数据，我们通过计算特定于基因的突变容忍度得分，展示了如何通过基因而不是变体来进行优先级排序。我们还使用五个典范示例说明了突变结构对变体优先级排序的影响。最后，我们讨论了家族变异分析作为变体优先级排序的最后一步的重要性。
