Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

Original languageEnglish
Pages (from-to)209-220
Number of pages12
JournalNature Genetics
Volume55
Issue number2
DOIs
StatePublished - 1 Feb 2023

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