PDF(Pubmed)
Abstract：
BACKGROUND: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics.
RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic\'s Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A).
CONCLUSIONS: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP\'s limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic\'s Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A).
CONCLUSIONS: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP\'s limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
摘要：
背景：尽管下一代测序（NGS）测试如外显子组测序（ES），基因组测序（GS），来自外显子组和基因组数据（EGBP）的面板对罕见疾病有效，理想的诊断方法存在争议。有限的研究已经探索重新分析原始ES和GS数据后阴性EGBP结果以进行诊断。
结果：我们分析了来自MayoClinic的罕见和未诊断疾病计划（PRaUD）患者的完整ES/GS原始测序数据，以评估补充结果是否可以提高诊断率。来自80名患者（59名成人）的ES数据和来自20名患者（10名成人）的GS数据，平均年龄43岁,进行了分析。大多数患者具有肾脏（n=44）和自身炎症（n=29）表型。96例发现阴性，其中4例发现了其他遗传变异，包括与最近描述的疾病（RRAGD相关的低镁血症）相关的变体，由于不一致的继承模式(COL4A3)而错过的变体，在一般人群中具有高等位基因频率（NPHS2）的变体，和与最初未靶向的表型(HNF1A)相关的变体。
结论：ES和GS对单系统疾病的诊断率与EGBP相当。然而,EGBP在检测新的疾病相关基因方面的局限性强调了定期更新的必要性。
结果：我们分析了来自MayoClinic的罕见和未诊断疾病计划（PRaUD）患者的完整ES/GS原始测序数据，以评估补充结果是否可以提高诊断率。来自80名患者（59名成人）的ES数据和来自20名患者（10名成人）的GS数据，平均年龄43岁,进行了分析。大多数患者具有肾脏（n=44）和自身炎症（n=29）表型。96例发现阴性，其中4例发现了其他遗传变异，包括与最近描述的疾病（RRAGD相关的低镁血症）相关的变体，由于不一致的继承模式(COL4A3)而错过的变体，在一般人群中具有高等位基因频率（NPHS2）的变体，和与最初未靶向的表型(HNF1A)相关的变体。
结论：ES和GS对单系统疾病的诊断率与EGBP相当。然而,EGBP在检测新的疾病相关基因方面的局限性强调了定期更新的必要性。
