Department of Genetics, Children's University Hospital, Dublin, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Epilepsia. 2014 Jun;55(6):858-65. doi: 10.1111/epi.12645. Epub 2014 May 14.
To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.
We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment.
A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2.
A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
在两组不一致的同卵双胞胎和 11 例孤立病例中，确定 Landau-Kleffner 综合征（LKS）的遗传基础。
我们采用多方面的方法来鉴定 LKS 的遗传风险因素。使用 Agilent 180K 阵列进行阵列比较基因组杂交（CGH）。在两个不一致的双胞胎、三个孤立的 LKS 病例和 12 个对照样本中使用 Illumina 27K 阵列进行全基因组甲基化谱分析。对 13 例 LKS 患者（包括两组不一致的 MZ 双胞胎）进行外显子组测序。对新发和罕见变异、重叠基因、报道的癫痫基因中的变异以及通路富集进行分析。
在单个患者的 GRIN2A 基因中发现了一个变异（cG1553A），导致 518 位精氨酸变为组氨酸，这是一个预测的谷氨酸结合位点。在进行拷贝数变异（CNV）、甲基化和外显子组测序分析后，在剩余队列中没有发现单一候选基因导致 LKS。然而，确定了一些有趣的额外候选变异，包括 RELN、BSN、EPHB2 和 NID2 基因中的变异。
在 GRIN2A 基因中鉴定出一个单一突变。本研究确定了一些额外的候选基因，包括 RELN、BSN、EPHB2 和 NID2。本文的幻灯片总结可在此处的支持信息部分下载。
