Hemimegalencephaly study with WXS data on dbGaP (52 participants)

phs002156 — Molecular Characterization of Hemimegalencephaly

Somatic mutations, in which a fraction of the cells in the body have a deleterious mutation, are well recognized in cancer but only recently appreciated in neurological disease. Given a somatic mutation in a population of progenitor cells, all daughter cells inherit the mutation and are able to express the resultant phenotype as a function of the differentiation program. We recently identified the first de novo somatic mutations in the developing brain in the condition hemimegalencephaly (HME), a catastrophic focal epilepsy condition associated with a malformation of cerebral cortical development (MCD). HME is one of the most severe MCD syndromes, characterized by massive hamartomatous overgrowth of either of the two cerebral hemispheres. Cerebral hemispherectomy is a frequent treatment for refractory epilepsy, allowing the sampling of diseased tissue. By comparing DNA from a diseased brain with DNA from blood/saliva, we identified de novo somatic mutations in <a href="https://www.ncbi.nlm.nih.gov/gene/5290">PIK3CA</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/10000">AKT3</a> or <a href="https://www.ncbi.nlm.nih.gov/gene/2475">MTOR</a>, part of the mTOR pathway. Mutations were present in 8-40% of sequenced alleles in various brain regions sampled during surgery and in some codons known to activate proteins.• Population information Patient samples were collected from multiple centers. The population is Caucasian and Hispanic• Molecular technologies employed Whole-exome sequencing• Principal findings of the study We were the first to describe mTOR-related and non-mTOR mutations causing hemimegalencephaly, and we described two-hit mutational models to explain the genetic pathogenesis of hemimegalencephaly