Abstract
We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets.
Highlights
The Epileptic Encephalopathies are a clinically and etiologically heterogeneous group of devastating infantile and childhood-onset epilepsies, broadly characterized by refractory seizures and developmental slowing or regression [1]
Selection of reference and candidate Epileptic Encephalopathy gene sets The 29 reference Epileptic Encephalopathy genes were all represented on the Allen Human Brain Atlas (AHBA) gene expression array and in the Celsius resource accessed via UGET
Of the 182 candidate genes, C15orf-AP3S2, TNNI3K, WHSCIL1 were not present on the AHBA array, nor could alternative gene names be found for them, they were excluded from the analysis, leaving 179 candidate Epileptic Encephalopathy genes
Summary
The Epileptic Encephalopathies are a clinically and etiologically heterogeneous group of devastating infantile and childhood-onset epilepsies, broadly characterized by refractory seizures and developmental slowing or regression [1]. Following the seminal discovery of de novo SCN1A mutations as the cause in .80% of patients with Dravet syndrome [2], a paradigmatic epileptic encephalopathy, a number of other genes have been shown to account for other hitherto unexplained Epileptic Encephalopathies [3,4,5,6]. Parallel sequencing has recently accelerated gene discovery, revealed unexpected genetic heterogeneity and cemented the role played by de novo mutations in causing Epileptic Encephalopathies. Carvill and colleagues [3] recently performed targeted massively parallel re-sequencing of 19 known and 46 candidate genes in 500 Epileptic Encephalopathy cases. They identified pathogenic mutations in 10% of patients in their cohort and established CHD2 and SYNGAP1 as novel Epileptic Encephalopathy genes. Another study employed a whole exome sequencing ‘trio design’ of 264 probands with
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