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, and causing 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 associating distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains implicate critical roles in excitatory neurogenic pools during brain development, and in promoting neuronal hyperexcitability after birth.

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitabilityviaoveractivation of neuronal GluN2C NMDA receptors

“…The data obtained here make it the GluN2C-containing NMDAR a possible target in FCD type II caused by somatic variants of the mTOR pathway, as also previously suggested for autosomal dominant TSC (Gataullina et al, 2022; Lozovaya et al, 2014). The importance of GluN2C in the pathogenesis of FCD might even expand beyond the spectrum of mTORopathies, as very recently suggested by the detection of a likely pathogenic, somatic GRIN2C variant in a patient with FCD type I (Chung et al, 2023). Our results also indicated that the GluN2C anomalies observed in our model of FCD followed the same developmental pattern as for Tsc +/- mice, suggesting the existence of a critical time window for GluN2C-mediated pathomechanisms and for related rescue strategies.…”

An adhesion signaling axis involving Dystroglycan, β1-Integrin and Cas adaptor proteins regulates the establishment of the cortical glial scaffold

“…The striking resemblance of the phenotypes observed in cortical CasTcKOs and patients with cobblestone lissencephaly, in addition to the molecular epistasis experiments suggesting that Cas proteins act downstream of Dag1 and β1-Integrin in radial glial cells to maintain basement membrane integrity, pinpoint cytoplasmic effectors of adhesion signaling as possible contributing factors to the etiology of these neurodevelopmental disorders. A recent study revealed that several genes involved in regulating cell-matrix adhesion and IAC assembly are somatically mutated in patients with Focal Cortical Dysplasia [161]. Patients with FCD type I show disruptions of the cortical laminar structure that parallel those observed in Type II lissencephaly, but as the name implies, these dysplasia are more focal in nature, i.e.…”

Deciphering the role of somatic variant accumulation and brain mosaicism in Alzheimer disease pathogenesis

“…On the other hand, the "protected" sites are regions of the genome that are less likely to undergo genetic changes. While it is noticing that these regions might be more effectively repaired when damage occurs, or they might be less exposed to factors that cause DNA damage, scientists have not identified the locations of these regions clearly and understand the molecular basis of how these changes in their studies [4,17,18].…”