NG: Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
In this video introduction, Drs. Changuk Chung and Xiaoxu Yang from Dr. Joseph Gleeson's lab are presenting genetic and clinical discoveries in the malformation of cortical development. Malformation of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, primarily 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 the authors report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining state-of-the-art mutation detection technologies involving deep learning on 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.
For more information, please visit the original publication at https://www.nature.com/articles/s4158...