The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a “diagnostic odyssey.” An increase in the variability of genetic disorders and the corresponding gene‐disease associations suggest the need to periodically re‐evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73–3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.

中文翻译：

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复杂神经遗传疾病的奥德赛：从不确定到积极

神经遗传疾病的遗传和表型异质性迫使患者及其家人陷入“诊断奥德赛”。遗传疾病变异性和相应基因-疾病关联的增加表明需要定期重新评估未确定致病性变异的重要性。在这里，我们报告了过去 4 年里，来自布宜诺斯艾利斯和辛辛那提中心的 341 名疑似神经遗传性疾病患者的靶向基因组测序 (TGPS) 和全外显子组测序 (WES) 的诊断和临床效用，重点是重新解释的有用性以前被归类为具有不确定意义的变体。在平均 ±2 年 (IC 95:0.73–3.27) 后，大约 30% 意义不确定的变异被重新归类为致病变异。下一代测序方法的使用促进了生殖系和嵌合体致病变异的鉴定，扩大了诊断率。这些结果证明了对临床神经病学中未确定变异的定期重新分析具有很高的临床影响。