GeneDx, Gaithersburg, MD, USA.
Epilepsia. 2018 May;59(5):1062-1071. doi: 10.1111/epi.14074. Epub 2018 Apr 14.
We evaluated >8500 consecutive, unselected patients with epilepsy and neurodevelopmental disorders who underwent multigene panel testing to determine the average age at molecular diagnosis and diagnostic yield of 70 genes.
We reviewed molecular test results for 70 genes known to cause epilepsy and neurodevelopmental disorders using next generation sequencing (NGS) and exon-level array comparative genomic hybridization (aCGH). A positive result was defined as the presence of 1 or 2 pathogenic or likely pathogenic (P/LP) variants in a single gene, depending on the mode of inheritance of the associated disorder.
Overall, 22 genes were found to have a high yield of positive findings by genetic testing, with SCN1A and KCNQ2 accounting for the greatest number of positive findings. In contrast, there were no positive findings in 16 genes. Most of the P/LP variants were sequence changes identified by NGS (90.9%), whereas ~9% were gross deletions or duplications detected by exon-level aCGH. The mean age of molecular diagnosis for the cohort was 5 years, 8 months (ranging from 1 week to 47 years). Recurrent P/LP variants were observed in 14 distinct genes, most commonly in MECP2, KCNQ2, SCN1A, SCN2A, STXBP1, and PRRT2. Parental testing was performed in >30% of positive cases. All variants identified in CDKL5, STXBP1, SCN8A, GABRA1, and FOXG1 were de novo, whereas 85.7% of variants in PRRT2 were inherited.
Using a combined approach of NGS and exon-level aCGH, testing identified a genetic etiology in 15.4% of patients in this cohort and revealed the age at molecular diagnosis for patients. Our study highlights both high- and low-yield genes associated with epilepsy and neurodevelopmental disorders, indicating which genes may be considered for molecular diagnostic testing.
我们评估了 >8500 例连续的、未经选择的癫痫和神经发育障碍患者，这些患者接受了多基因panel 检测，以确定分子诊断的平均年龄和 70 个基因的诊断产量。
我们使用下一代测序（NGS）和外显子水平的 array 比较基因组杂交（aCGH）回顾了 70 个已知引起癫痫和神经发育障碍的基因的分子检测结果。阳性结果定义为在单个基因中存在 1 或 2 个致病性或可能致病性（P/LP）变异，具体取决于相关疾病的遗传模式。
总体而言，22 个基因的基因检测阳性发现率较高，其中 SCN1A 和 KCNQ2 导致的阳性发现最多。相比之下，有 16 个基因没有阳性发现。大多数 P/LP 变异是通过 NGS 识别的序列变化（90.9%），而约 9%是通过外显子水平 aCGH 检测到的大片段缺失或重复。该队列的分子诊断平均年龄为 5 岁 8 个月（范围为 1 周至 47 岁）。在 14 个不同的基因中观察到复发性 P/LP 变异，最常见的是 MECP2、KCNQ2、SCN1A、SCN2A、STXBP1 和 PRRT2。在 >30%的阳性病例中进行了父母检测。在 CDKL5、STXBP1、SCN8A、GABRA1 和 FOXG1 中鉴定的所有变异均为新生变异，而 PRRT2 中的 85.7%变异是遗传的。
使用 NGS 和外显子水平 aCGH 的联合方法，在该队列的患者中检测出了 15.4%的遗传病因，并揭示了患者的分子诊断年龄。我们的研究突出了与癫痫和神经发育障碍相关的高产量和低产量基因，表明哪些基因可能被考虑用于分子诊断检测。
