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Title: Somatic mutation: The hidden genetics of brain malformations and focal epilepsies.
Austin Authors: Ye, Zimeng;McQuillan, Lara ;Poduri, Annapurna;Green, Timothy E;Matsumoto, Naomichi;Mefford, Heather C;Scheffer, Ingrid E ;Berkovic, Samuel F ;Hildebrand, Michael S 
Affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia
Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, MA, United States
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, United States
Issue Date: Sep-2019
Date: 2019-07-02
Publication information: Epilepsy Research 2019; 155: 106161
Abstract: Over the past decade there has been a substantial increase in genetic studies of brain malformations, fueled by the availability of improved technologies to study surgical tissue to address the hypothesis that focal lesions arise from focal, post-zygotic genetic disruptions. Traditional genetic studies of patients with malformations utilized leukocyte-derived DNA to search for germline variants, which are inherited or arise de novo in parental gametes. Recent studies have demonstrated somatic variants that arise post-zygotically also underlie brain malformations, and that somatic mutation explains a larger proportion of focal malformations than previously thought. We now know from studies of non-diseased individuals that somatic variation occurs routinely during cell division, including during early brain development when the rapid proliferation of neuronal precursor cells provides the ideal environment for somatic mutation to occur and somatic variants to accumulate. When confined to brain, pathogenic variants contribute to the "hidden genetics" of neurological diseases. With burgeoning novel high-throughput genetic technologies, somatic genetic variations are increasingly being recognized. Here we discuss accumulating evidence for the presence of somatic variants in normal brain tissue, review our current understanding of somatic variants in brain malformations associated with lesional epilepsy, and provide strategies to identify the potential contribution of somatic mutation to non-lesional epilepsies. We also discuss technologies that may improve detection of somatic variants in the future in these and other neurological conditions.
DOI: 10.1016/j.eplepsyres.2019.106161
ORCID: 0000-0002-2311-2174
Journal: Epilepsy Research
PubMed URL: 31295639
Type: Journal Article
Subjects: Brain malformations
Deep sequencing
Lesional epilepsies
Somatic mosaicism
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