Brain. 2017 Aug 1;140(8):2144-2156. doi: 10.1093/brain/awx129.
Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.
癫痫的基因鉴定主要局限于分离具有主要效应基因的大家族以及癫痫性脑病中的新生突变。许多患有常见非后天性局灶性癫痫和遗传性全身性癫痫的家族病因仍未明确。我们通过收集和对包含多个无诱因发作个体的家族进行表型分析，组建了一组“基因富集”的常见癫痫患者队列。我们旨在确定特定的临床癫痫特征是否在家族中聚集，以及这种表型分离是否可能构成不同的“家族综合征”，从而为基因组分析提供依据。多个国际中心对有三名或更多无诱因发作个体的家族进行了研究。根据特定的电临床综合征对受影响个体进行表型分析和分类。根据受影响家庭成员的综合征分组对家族进行分类，检查系谱结构和表型模式，并在可能的情况下指定特定的家族性癫痫综合征。总共组建并分析了303个家族，包括1120名有表型的受影响个体。在这303个家族中，117个家族仅分离出全身性癫痫，62个家族为局灶性癫痫，22个家族被归类为伴有热性惊厥附加症的遗传性癫痫。超过三分之一（102个家族）被观察到具有混合性癫痫表型：78个家族在同一个体（n = 39）或一级或二级亲属中同时具有全身性和局灶性癫痫特征（n = 39）。在遗传性全身性癫痫家族中，失神癫痫在家族中聚集，与青少年肌阵挛癫痫无关，且受影响的女性明显多于男性。在62个家族性局灶性癫痫家族中，有两种先前未描述的家族性局灶综合征模式明显：15个家族患有后象限癫痫，其中7个具有枕颞定位，7个具有颞顶叶病灶，4个家族表现为儿童期家族性局灶性癫痫，有多个受影响的兄弟姐妹，提示隐性遗传。研究结果表明：（i）存在综合征性家族聚集的特定模式，包括新发现的家族性局灶性癫痫形式；（ii）尽管综合征特异性通常发生在多个成员的家族中，但三分之一具有局灶性和全身性癫痫特征的家族提示存在共同的遗传决定因素；（iii）在家族中观察到的特征模式，包括系谱结构、性别和发病年龄，可能为未来的基因鉴定提供线索。这些详细的表型信息对于即将到来的测序数据的预处理和解读，以了解常见癫痫综合征的遗传结构和相互关系将具有重要价值。
