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Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia
Author(s) -
D'Gama Alissa M.,
Geng Ying,
Couto Javier A.,
Martin Beth,
Boyle Evan A.,
LaCoursiere Christopher M.,
Hossain Amer,
Hatem Nicole E.,
Barry Brenda J.,
Kwiatkowski David J.,
Vinters Harry V.,
Barkovich A. James,
Shendure Jay,
Mathern Gary W.,
Walsh Christopher A.,
Poduri Annapurna
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24357
Subject(s) - hemimegalencephaly , cortical dysplasia , epilepsy , exome sequencing , germline , megalencephaly , pi3k/akt/mtor pathway , dysplasia , biology , gene , mutation , neuroscience , pathology , medicine , cancer research , genetics , signal transduction
Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation‐associated epilepsy. Ann Neurol 2015;77:720–725