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

ABSTRACT: Malformations of cortical development (MCD) are neurological conditions displaying focal disruption of cortical architecture and cellular organization arising during embryogenesis, largely from somatic mosaic mutations. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fraction in brain tissue resected to treat epilepsy. Here, we report genetic atlas from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation and single-cell sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associating distinct pathophysiological and clinical phenotypes. Moreover, the unique spatiotemporal expression patterns deconvolved from single-nuclear transcriptional sequences of mutated genes in control and patient brains suggest critical roles driving excitatory neurogenic pools during brain development, and in establishing neuronal excitation after birth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218022 | GEO | 2022/11/17

REPOSITORIES: GEO

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