小脑共济失调及相关神经系统疾病外显子组测序的诊断上限(2006)

摘要目的:鉴于目前技术和生物信息学方法的进展，评估全外显子组测序(WES)对小脑性共济失调和相关神经退行性疾病的诊断价值。

背景:遗传共济失调与数百个基因的突变有关，这些基因具有高表型重叠，使临床诊断复杂化。全外显子组测序大大提高了所有患者的总体诊断率。然而，这种方法的上限仍然不明确，阻碍了解决剩余诊断差距的努力。

设计/方法:为了进一步评估罕见编码变异在共济失调疾病中的作用，我们重新分析了之前发表的76例主要为成人和散发性发病患者的外显子组队列，将病例总数扩大到260例，并在一个代表性子集中引入了拷贝数变异和重复扩增的分析。

结果:对于新病例(n=184)，我们的结果临床相关检出率保持稳定在47%，其中24%被归类为致病性。对先前测序的76例患者的重新分析使致病性略微提高了7%。在联合队列(n=260)中，观察到的总临床检出率为52%，其中25%为致病性。已发表的类似神经表型的研究报告了相似的发病率。

结论:多个队列中诊断率的一致性表明，鉴于我们目前对分子发病机制的了解，尽管技术和分析不断进步，50%的诊断率可能标志着当前基于wes的方法的相对上限，需要更全面的全基因组评估来确定小脑性共济失调和相关神经退行性疾病缺失的致病遗传病因。

披露:吴医生没什么可透露的。雷克萨奇医生没什么可透露的。李博士没有什么要透露的。佩蒂医生没有什么要透露的。我曾在瑞塔制药的足总顾问委员会任职。我曾担任Biohaven Pharma, Erydel Pharma, Reata Pharma和武田制药赞助的药物试验的现场PI。瓦莱拉没有什么要透露的。迪尼昂医生没有什么要透露的。毛博士没有什么可透露的。阿克博士没有什么要透露的。 Dr. Posey has nothing to disclose. Dr. Jhangiani has nothing to disclose. Dr. Akdemir has nothing to disclose. Dr. Boerwinkle has nothing to disclose. Dr. Muzny has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Hassin has nothing to disclose. Dr. Poke has nothing to disclose. Dr. Neas has nothing to disclose. Dr. Geschwind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adept Field Consulting, 3M Communications, Grand Rounds Inc., Best Doctors Inc., BPP Inc, and Anderson Boutwell Traylor.Dr. Grody has nothing to disclose. Dr. Gibbs has nothing to disclose. Dr. Geschwind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ovid Therapeutics, Axial Biotherapeutics, and Falcon Computing. Dr. Geschwind has received personal compensation in an editorial capacity for Biological Psychiatry and NYAS. Dr. Geschwind has received research support from Roche and Takeda Pharmaceutical. Dr. Lupski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Baylor Genetics. Paid consultant for Regeneron Pharmaceuticals.. Dr. Lupski has received compensation for serving on the Board of Directors of Stock ownership in 23andMe. Dr. Lupski has received royalty, license fees, or contractual rights payments from Co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. Dr. Below has nothing to disclose. Dr. Nelson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Nelson has received research support from PTC Therapeutics, Inc. Dr. Fogel has nothing to disclose.