Application of single cell genomics to focal epilepsies: A call to action

Abstract

Focal epilepsies are the largest epilepsy subtype and associated with significant morbidity. Somatic variation is a newly recognized genetic mechanism underlying a subset of focal epilepsies, but little is known about the processes through which somatic mosaicism causes seizures, the cell types carrying the pathogenic variants, or their developmental origin. Meanwhile, the inception of single cell biology has completely revolutionized the study of neurological diseases and has the potential to answer some of these key questions. Focusing on single cell genomics, transcriptomics, and epigenomics in focal epilepsy research, circumvents the averaging artifact associated with studying bulk brain tissue and offers the kind of granularity that is needed for investigating the consequences of somatic mosaicism. Here we have provided a brief overview of some of the most developed single cell techniques and the major considerations around applying them to focal epilepsy research.

The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission

“…Analysis of pools of microdissected cells demonstrated that dysmorphic neurons and balloon cells carry the pathogenic variants leading to hyperactivation of mTOR 19,51,64 . These discoveries offer the opportunity to reshape the genetic landscape of FCD, distinguishing mTOR and non–mTOR‐related FCD toward a new integrated genotype–phenotype classification 12,13,66 . The current challenge is whether genetic findings can predict surgery outcome, the extent of the lesion, and the presence of multiple or bilateral lesions 67 .…”

“…19,51,64 These discoveries offer the opportunity to reshape the genetic landscape of FCD, distinguishing mTOR and non-mTOR-related FCD toward a new integrated genotypephenotype classification. 12,13,66 The current challenge is whether genetic findings can predict surgery outcome, the extent of the lesion, and the presence of multiple or bilateral lesions. 67 Overall mTOR-related MCD with germline or germline and somatic variants have a better surgical outcome than MCD caused by mutations in ion channel and synaptic transmission genes.…”

Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains

“…Taken together, it is highly likely that somatic mutation AKT1 E17K might occur during the stage of progenitor cells of the bilateral dorsal forebrain with unique spatio-temporal gradients. 6,15 The PIK3CA, AKT1, and MTOR genes encode wellknown regulators of the mTOR signaling pathway, which is involved in cell growth and metabolism, [4][5][6] and its activation is observed in apical progenitor cells and the cortical plate in developing murine cerebral cortex, suggesting that this signaling is involved in multiple steps of cerebral development, including cell proliferation, differentiation of stem/progenitor cells, and migration in cortical development. 2 In cases 1 and 2, we observed that cell nests immunoreactive for P-RPS6 (Ser240/244) were scattered in the polymicrogyria-like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K-AKT-MTOR pathway was actually activated in these cells.…”

Recent advances and application of whole genome amplification in molecular diagnosis and medicine

“…Moreover, its experimental operation is more tedious and lacks repeatability. 77 Therefore, the future development of LIANTI needs to be further explored.…”

“…It is highly dependent on Tn5 transposase and has not yet achieved large‐scale application. Moreover, its experimental operation is more tedious and lacks repeatability 77 . Therefore, the future development of LIANTI needs to be further explored.…”