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Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K\u2010AKT\u2010MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype\u2013phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and\/or autism spectrum disorder; moderately activating variants (that are typically high\u2010level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low\u2010level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K\u2010AKT\u2013MTOR pathway inhibitors.<\/jats:p>","DOI":"10.1002\/ajmg.c.31736","type":"journal-article","created":{"date-parts":[[2019,8,23]],"date-time":"2019-08-23T05:44:21Z","timestamp":1566539061000},"page":"582-590","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Megalencephaly syndromes associated with mutations of core components of the PI3K\u2010AKT\u2013MTOR pathway:\n                    <i>PIK3CA<\/i>\n                    ,\n                    <i>PIK3R2<\/i>\n                    ,\n                    <i>AKT3<\/i>\n                    , and\n                    <i>MTOR<\/i>"],"prefix":"10.1002","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-2844","authenticated-orcid":false,"given":"William B.","family":"Dobyns","sequence":"first","affiliation":[{"name":"University of Washington School of Medicine  Seattle Washington"},{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-7657","authenticated-orcid":false,"given":"Ghayda M.","family":"Mirzaa","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine  Seattle Washington"},{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,23]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx203"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-009-0160-5"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0929-8266(00)00099-9"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00302232"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02777.x"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2008.10.010"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019605-199710000-00001"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320350231"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.22.6.634"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0887-8994(86)90072-X"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.029"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32515"},{"key":"e_1_2_5_14_1","first-page":"230","article-title":"A case of megalencephaly","volume":"51","author":"Fletcher H. 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