☆ 4.6 Article

Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY (2019)

Journal

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY

Volume 6, Issue 7, Pages 1338-1344

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WILEY

DOI: 10.1002/acn3.50815

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Clinical Neurology Neurosciences

Funding

Australian Government National Health and Medical Research Council [GNT1128933]
Murdoch Children's Research Institute
Campbell Edwards Trust
Brain Foundation
Independent Research Institute Infrastructure Support Scheme
Victorian State Government Operational Infrastructure Program
Melbourne Children's Clinician Scientist Fellowship scheme

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Abstract

Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic 2-hit model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug-resistant epilepsy and refine conceptualization of the epileptogenic zone.

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Hande Caglayan, Mutluay Arslan, Zuhal Yapici, Pinar Topaloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asli Gundogdu-Eken, Nerses Bebek, Sibel Ugur-Iseri, Betul Baykan, Baris Salman, Garen Haryanyan, Emrah Yucesan, Yesim Kesim, Cigdem Ozkara, Meng-Han Tsai, Chen-Jui Ho, Chih-Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Dennis Lal, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Dennis J. Dlugos, Warren Lo, Michael Privitera, Jacqueline A. French, Patrick Cossette, Steven Schachter, Hakon Hakonarson, Daniel H. Lowenstein, Ruben I. Kuzniecky, Dennis J. Dlugos, Orrin Devinsky, Daniel H. Lowenstein, Ruben I. Kuzniecky, Jacqueline A. French, Manu Hegde, David A. Greenberg, Ingo Helbig, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, David Lewis-Smith, Mahgenn Cosico, Priya Vaidiswaran, Eryn Fitch, Charles R. J. C. Newton, SymonM. Kariuki, Ryan G. Wagner, Seth Owusu-Agyei, Andrew J. Cole, ChristopherM. McGraw, S. Anthony Siena, Lea Davis, Donald Hucks, Annika Faucon, David Wu, Bassel W. Abou-Khalil, Kevin Haas, Randip S. Taneja

Summary: In this study, the authors conducted a meta-analysis involving 26,699 individuals with seizure disorders and 492,324 population controls, and identified 25 genome-wide significant copy-number variants (CNVs). These findings provide new insights into the genetic risk factors for epilepsy and related seizure disorders, and may have implications for clinical practice.

NATURE COMMUNICATIONS (2023)

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Article Clinical Neurology

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Alissa M. D'Gama, Sarah Mulhern, Beth R. Sheidley, Fadil Boodhoo, Sarah Buts, Natalie J. Chandler, Joanna Cobb, Meredith Curtis, Edwardj Higginbotham, Jonathon Holland, Tayyaba Khan, Julia Koh, Nicole S. Yliang, Lyndsey Mcrae, Sarah E. Nesbitt, Brandon T. Oby, Ben Paternoster, Alistair Patton, Graham Rose, Elizabeth Scotchman, Rozalia Valentine, Kimberly N. Wiltrout, Robin Z. Hayeems, Puneet Jain, Sebastian Lunke, Christian R. Marshall, Shira Rockowitz, Neilj Sebire, Zornitza Stark, Susan M. White, Lyn S. Chitty, J. Helen Cross, Ingrid E. Scheffer, Vann Chau, Gregory Costain, Annapurna Poduri, Katherine B. Howell, Amy McTague

Summary: A cohort study was conducted to determine the feasibility and clinical utility of rapid genome sequencing in infants with new-onset epilepsy. Among 100 infants enrolled in the study, genetic diagnoses were identified in 43% of the cases. Rapid genome sequencing had immediate clinical impact on treatment, evaluation, prognosis, and recurrence risk counselling.

LANCET NEUROLOGY (2023)

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Article Clinical Neurology

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy

Chaseley E. McKenzie, Ian C. Forster, Ming S. Soh, A. Marie Phillips, Lauren E. Bleakley, Sophie J. Russ-Hall, Kenneth A. Myers, Ingrid E. Scheffer, Christopher A. Reid

Summary: This study describes the functional analysis of seven pathogenic variants of HCN1 occurring in the transmembrane domain. A common cation leak characteristic was identified in all seven variants, suggesting that cation leak is an important pathogenic mechanism in HCN1 developmental and epileptic encephalopathy.

BRAIN COMMUNICATIONS (2023)

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