Fanciulli Manuela, Pasini Elena, Malacrida Sandro, Striano Pasquale, Striano Salvatore, Michelucci Roberto, Ottman Ruth, Nobile Carlo
Porto Conte Ricerche, Alghero, Italy.
Epilepsia. 2014 Oct;55(10):1651-8. doi: 10.1111/epi.12767. Epub 2014 Sep 19.
Autosomal dominant lateral temporal epilepsy (ADLTE) is a focal epileptic syndrome characterized by auditory or aphasic auras. Mutations in the LGI1 gene account for <50% of ADLTE families. To identify copy number variants (CNVs) related to ADLTE, we examined a collection of ADLTE families without LGI1 mutations.
Twenty-one families were included based on a history of focal seizures with auditory and/or receptive aphasic symptoms in two or more individuals, absence of brain abnormalities, and negative LGI1 test. DNA suitable for single nucleotide polymorphism-array analysis was genotyped using the high-density HumanOmni1-Quad v1.0 beadchip (Illumina). CNVs were inferred using the PennCNV algorithm. Selected CNVs were validated by real-time quantitative polymerase chain reaction (qPCR).
We analyzed 62 affected and 114 unaffected members of our study families and identified a total of 11,214 CNVs, corresponding to 1,890 unique regions with an average size of 67.3 kb. Most CNVs were <50 kb, whereas a small proportion (1.2%) exceeded 500 kb. We identified 12 rare CNVs that segregated with lateral temporal epilepsy in single families. Particularly, we found rare microdeletions within or near two genes, RBFOX1 and NRXN1, previously shown to harbor deletions associated with idiopathic generalized epilepsy, and a microduplication in the proximal region of chromosome 1q21.1, where duplications have been associated with various neurodevelopmental disorders and epilepsy. We also found numerous polymorphic CNVs in the affected members of one or more families, including a deletion of the PCDHA8/10 genes, which was enriched in the patients of our family cohort.
Our results provide clues on genes for susceptibility to ADLTE, particularly in those families where the inheritance pattern is less compatible with autosomal dominance. Some of these genes also confer risk for other epilepsy syndromes.
常染色体显性遗传性外侧颞叶癫痫（ADLTE）是一种以听觉或失语性先兆为特征的局灶性癫痫综合征。LGI1基因突变在ADLTE家族中所占比例不到50%。为了鉴定与ADLTE相关的拷贝数变异（CNV），我们对一组无LGI1突变的ADLTE家族进行了检测。
纳入21个家族，这些家族中两个或更多个体有局灶性发作史，伴有听觉和/或感受性失语症状，无脑异常，且LGI1检测为阴性。使用高密度HumanOmni1-Quad v1.0芯片（Illumina）对适合单核苷酸多态性阵列分析的DNA进行基因分型。使用PennCNV算法推断CNV。通过实时定量聚合酶链反应（qPCR）对选定的CNV进行验证。
我们分析了研究家族中的62名患者和114名未患病成员，共鉴定出11214个CNV，对应于1890个独特区域，平均大小为67.3 kb。大多数CNV小于50 kb，而一小部分（1.2%）超过500 kb。我们在单个家族中鉴定出12个与外侧颞叶癫痫共分离的罕见CNV。特别是，我们在两个基因RBFOX1和NRXN1内部或附近发现了罕见的微缺失，此前已显示这两个基因存在与特发性全身性癫痫相关的缺失，以及1q21.1染色体近端区域的一个微重复，该区域的重复与各种神经发育障碍和癫痫有关。我们还在一个或多个家族的患病成员中发现了许多多态性CNV，包括PCDHA8/10基因的缺失，该缺失在我们家族队列的患者中富集。
我们的结果为ADLTE易感性基因提供了线索，特别是在那些遗传模式与常染色体显性遗传不太相符的家族中。其中一些基因也会增加患其他癫痫综合征的风险。
