Epilepsy and the new cytogenetics.

We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase-dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the last half a decade, and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome-wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to nonallelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of ∼ 1% at 15q13.3, 16p13.11, and 15q11.2, sites that also confer susceptibility for intellectual disability, autism, and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counseling. CNVs play a significant role in the susceptibility profile for epilepsies, with complex genetics and their comorbidities both from the "hotspots" defined by segmental duplication and elsewhere in the genome where their location and size are often novel.

Mulley JC ，Mefford HC 《-》

Copy number variants are frequent in genetic generalized epilepsy with intellectual disability.

Mullen SA ，Carvill GL ，Bellows S ，Bayly MA ，Trucks H ，Lal D ，Sander T ，Berkovic SF ，Dibbens LM ，Scheffer IE ，Mefford HC ... -  《-》

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies.

de Kovel CG ，Trucks H ，Helbig I ，Mefford HC ，Baker C ，Leu C ，Kluck C ，Muhle H ，von Spiczak S ，Ostertag P ，Obermeier T ，Kleefuss-Lie AA ，Hallmann K ，Steffens M ，Gaus V ，Klein KM ，Hamer HM ，Rosenow F ，Brilstra EH ，Trenité DK ，Swinkels ME ，Weber YG ，Unterberger I ，Zimprich F ，Urak L ，Feucht M ，Fuchs K ，Møller RS ，Hjalgrim H ，De Jonghe P ，Suls A ，Rückert IM ，Wichmann HE ，Franke A ，Schreiber S ，Nürnberg P ，Elger CE ，Lerche H ，Stephani U ，Koeleman BP ，Lindhout D ，Eichler EE ，Sander T ... -  《-》

Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies.

Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies and other neurodevelopmental disorders. The full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe associated phenotypes in a cohort of pediatric epilepsy patients. We screened 570 patients with pediatric epilepsies including idiopathic generalized epilepsies, focal epilepsies and fever-associated epilepsy syndromes for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. Identified microdeletions were confirmed using array comparative hybridization. Ten microdeletions in 15q11.2 (n=3), 15q13.3 (n=3) and 16p13.11 (n=4) were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. In our pediatric cohort, recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies or related EEG patterns. In contrast to previous reports, these recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a five-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data.

Jähn JA ，von Spiczak S ，Muhle H ，Obermeier T ，Franke A ，Mefford HC ，Stephani U ，Helbig I ... -  《-》

High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy.

Stewart LR ，Hall AL ，Kang SH ，Shaw CA ，Beaudet AL ... -  《BMC Medical Genetics》