A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders
A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders
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DOI：
10.1002/humu.23946
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发表时间：
2019-11-25
期刊：
影响因子：
3.9
通讯作者：
Fogel, Brent L.
中科院分区：
文献类型：
--
作者：
Ngo, Kathie J.;Rexach, Jessica E.;Fogel, Brent L.
遗传共济失调与数百个具有高表型重叠的基因突变有关，使临床诊断复杂化。全外显子组测序（WES）大大提高了总体诊断率。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。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。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。多个队列的一致性表明，尽管技术和分析不断进步，但大约50%的诊断率标志着当前基于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。
Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.