@article {998, title = {CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.}, journal = {Epilepsia}, year = {2021}, month = {2021 May 26}, abstract = {

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

}, issn = {1528-1167}, doi = {10.1111/epi.16931}, author = {Ernst, Michelle E and Baugh, Evan H and Thomas, Amanda and Bier, Louise and Lippa, Natalie and Stong, Nicholas and Mulhern, Maureen S and Kushary, Sulagna and Akman, Cigdem I and Heinzen, Erin L and Yeh, Raymond and Bi, Weimin and Hanchard, Neil A and Burrage, Lindsay C and Leduc, Magalie S and Chong, Josephine S C and Bend, Renee and Lyons, Michael J and Lee, Jennifer A and Suwannarat, Pim and Brilstra, Eva and Simon, Marleen and Koopmans, Marije and van Binsbergen, Ellen and Groepper, Daniel and Fleischer, Julie and Nava, Caroline and Keren, Boris and Mignot, Cyril and Mathieu, Sophie and Mancini, Grazia M S and Madan-Khetarpal, Suneeta and Infante, Elena M and Bluvstein, Judith and Seeley, Andrea and Bachman, Kristine and Klee, Eric W and Schultz-Rogers, Laura E and Hasadsri, Linda and Barnett, Sarah and Ellingson, Marissa S and Ferber, Matthew J and Narayanan, Vinodh and Ramsey, Keri and Rauch, Anita and Joset, Pascal and Steindl, Katharina and Sheehan, Theodore and Poduri, Annapurna and Vasquez, Alejandra and Ruivenkamp, Claudia and White, Susan M and Pais, Lynn and Monaghan, Kristin G and Goldstein, David B and Sands, Tristan T and Aggarwal, Vimla} } @article {503, title = {Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.}, journal = {Ann Neurol}, volume = {83}, year = {2018}, month = {2018 Jun}, pages = {1133-1146}, abstract = {

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.

METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.

RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17\%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14\%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53\%; Evidence for FCD was not observed in either brain tissue specimen.

INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

}, issn = {1531-8249}, doi = {10.1002/ana.25243}, author = {Winawer, Melodie R and Griffin, Nicole G and Samanamud, Jorge and Baugh, Evan H and Rathakrishnan, Dinesh and Ramalingam, Senthilmurugan and Zagzag, David and Schevon, Catherine A and Dugan, Patricia and Hegde, Manu and Sheth, Sameer A and McKhann, Guy M and Doyle, Werner K and Grant, Gerald A and Porter, Brenda E and Mikati, Mohamad A and Muh, Carrie R and Malone, Colin D and Bergin, Ann Marie R and Peters, Jurriaan M and McBrian, Danielle K and Pack, Alison M and Akman, Cigdem I and LaCoursiere, Christopher M and Keever, Katherine M and Madsen, Joseph R and Yang, Edward and Lidov, Hart G W and Shain, Catherine and Allen, Andrew S and Canoll, Peter D and Crino, Peter B and Poduri, Annapurna H and Heinzen, Erin L} }