Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela - IDIS, Santiago de Compostela, 15706, Spain.
Thyroid and Metabolic Diseases Unit (U.E.T.eM.), Department of Psychiatry, Radiology, Public Health, Nursing and Medicine (Medicine Area), Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS)-IDIS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Seizure. 2019 Oct;71:161-165. doi: 10.1016/j.seizure.2019.07.019. Epub 2019 Jul 25.
We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes.
Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry.
Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling.
Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.
我们报告了 2 例兄弟姐妹的病例，他们在 3 个月和 6 个月大时出现严重的难治性癫痫和神经退行性疾病。尽管进行了广泛的代谢和基因检测，包括使用针对癫痫基因的靶向下一代测序面板，但仍未能明确诊断。
对 2 例兄弟姐妹及其未受影响的父母进行全外显子组测序，此外还进行了成纤维细胞培养、RNA 提取和逆转录以及 cDNA PCR。对其中 1 名兄弟姐妹的脑组织进行了尸检，进行了神经病理学检查，包括组织学和免疫组织化学检查。
在 2 例兄弟姐妹中检测到 BSCL2 基因外显子 4 中的新生核苷酸变化（c.566T > A；p.（Met189Lys）），并通过 Sanger 测序证实。该变体在父母和第三个未受影响的兄弟姐妹中均不存在。
鉴于该变体的新生性质、其在公共和内部数据库中的缺失、我们的计算机预测致病性以及该变体与疾病表型的共分离，我们认为该新型变体与 2 例兄弟姐妹的癫痫性脑病表型相关。我们的发现首次提供了杂合性 BSCL2 变体与发育性和婴儿早期癫痫性脑病相关的证据。需要进一步的功能研究来阐明这种新的 BSCL2 相关表型的病理生理机制。
