Abstract：
BACKGROUND: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers.
METHODS: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria.
RESULTS: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1.
CONCLUSIONS: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.
METHODS: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria.
RESULTS: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1.
CONCLUSIONS: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.
摘要：
背景：下一代测序（NGS）极大地扩展了我们对多种癫痫综合征中遗传因素的理解，包括局灶性癫痫.描述常见综合征的遗传结构有望促进诊断过程，并有助于识别从基因检测中受益的患者，但是迄今为止，大多数研究仅限于检查患有智力障碍的儿童或成人。我们的目的是确定5个已建立的癫痫基因（DEPDC5，LGI1，SCN1A，GRIN2A,和PCHD19）在具有正常智力功能或轻度智力残疾的局灶性癫痫患者的广泛表型队列中，以及描述新的变体并确定变体载体的特征。
方法：对96例临床怀疑为遗传性局灶性癫痫的患者进行了靶向组测序。患者以前在神经内科诊所进行过全面的癫痫诊断评估，塞尔维亚大学临床中心。使用美国医学遗传学学会和分子病理学协会标准对感兴趣的变体(VOI)进行分类。
结果：在我们的队列中发现了8例（8/96，8.3%）患者中的6例VOI。在6例（6/96，6.2％）患者中确定了4种可能的致病性VOI，两名患者的两种DEPDC5变体，两名患者中有一个SCN1A变体，两名患者中有一个PCDH19变体。在一名（1/96，1.0％）患者的GRIN2A中发现了一种未知意义的变体（VUS）。GRIN2A中只有一个VOI被归类为可能的良性。在LGI1中未检测到VOI。
结论：仅对5个已知癫痫基因的测序在我们队列中的6.2%中产生了诊断结果，并揭示了多个新的变异。需要进一步的研究才能更好地了解智力正常或轻度智力残疾患者常见癫痫综合征的遗传基础。
方法：对96例临床怀疑为遗传性局灶性癫痫的患者进行了靶向组测序。患者以前在神经内科诊所进行过全面的癫痫诊断评估，塞尔维亚大学临床中心。使用美国医学遗传学学会和分子病理学协会标准对感兴趣的变体(VOI)进行分类。
结果：在我们的队列中发现了8例（8/96，8.3%）患者中的6例VOI。在6例（6/96，6.2％）患者中确定了4种可能的致病性VOI，两名患者的两种DEPDC5变体，两名患者中有一个SCN1A变体，两名患者中有一个PCDH19变体。在一名（1/96，1.0％）患者的GRIN2A中发现了一种未知意义的变体（VUS）。GRIN2A中只有一个VOI被归类为可能的良性。在LGI1中未检测到VOI。
结论：仅对5个已知癫痫基因的测序在我们队列中的6.2%中产生了诊断结果，并揭示了多个新的变异。需要进一步的研究才能更好地了解智力正常或轻度智力残疾患者常见癫痫综合征的遗传基础。
