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Epilepsy Exomes From Epi25 Project Lead to Mutation-Intolerant Gene Regions

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NEW YORK – The genes contributing to different forms of epilepsy appear to overlap, though more rare variants affecting mutation-intolerant regions of such genes seem to be overrepresented in individuals with severe forms of the disease, according to an ultra-rare variant analysis presented at the American Society of Human Genetics virtual meeting on Friday.

"This finding supports the hypothesis that the location of a missense variant, vis a vis, the intolerance of the surrounding genomic sequence may, in part, predict the severity of the resulting [epilepsy] phenotype," Joshua Motelow, a research fellow at the Columbia University Irving Medical Center's Institute for Genomic Medicine and a clinical fellow in pediatric critical care medicine at the New York Presbyterian Morgan Stanley Children's Hospital, reported there.

As part of the Epi25 Collaborative, an effort that brings together exome sequences and phenotypic information on more than 19,000 individuals with epilepsy including developmental and epileptic encephalopathies (DEE), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE), investigators from Columbia and Duke University analyzed protein-coding portions of the genome in 12,501 epilepsy cases and nearly 9,300 controls.

Consistent with prior studies pointing to a spectrum of somewhat overlapping genetic contributors in individuals with milder or more severe forms of epilepsy, the team found that both the location and type of mutation within a gene may in some cases influence its effect on epilepsy risk. In particular, the alterations turning up in individuals with a severe epilepsy subtype were more apt to carry rare variants in mutation-intolerant parts of a gene, known as "sub-genic intolerant" regions.

"Taken together, our study suggests that while multiple epilepsies may be caused by dysfunction in a shared set of genes, the severity of the epilepsy may be determined, in part, by the severity of the variant dictated by its location within the more intolerant regions of the gene," Motelow and his colleagues wrote in an abstract accompanying the conference presentation.

Building on interim rare variant results that members of the Epi25 consortium published last year, Motelow and colleagues clustered high-quality exome sequences from the participants with the help of SNP-based ancestry and population sub-structure clues. Within those clusters, in turn, they looked at base coverage and limited their analyses to bases with similar coverage to account for the methods used to generate the exomes.

"Our clustering method, which is being published shortly in another manuscript, more easily allows the incorporation of non-European populations," Motelow explained, adding that the current Epi25 analysis included individuals with African, East Asian, and admixed ancestry.

To search for rare variants contributing to one or more forms of epilepsy, the team assessed functional variants in genes across the case and control samples in each genetic cluster of participants.

Using regional intolerance analyses and a sub-genic intolerance filtering approach, Motelow explained, the researchers attempted to focus in on sub-genic sites with potential ties to DEE — a less common form of epilepsy that tends to be more severe and is typically diagnosed in younger individuals — or to more common, less severe forms of the disease such as NAFE and GGE.

The team uncovered ultra-rare protein-truncating or damaging missense mutations affecting new and known epilepsy genes in individuals with DEE, for example. In more than two dozen of the genes containing suspicious mutations in the DEE cases, subsequent analyses unearthed damaging ultra-rare variants linked to NAFE or GGE.

But changes in the overlapping genes appeared to turn up in different sub-genic regions depending on the type of epilepsy considered, Motelow reported, noting that "the distribution of DEE variants are significantly different from non-acquired focal epilepsy variants and trending toward different [distributions] compared to GGE."

That pattern seemed to hold when the investigators expanded their analysis to ultra-rare variants found in the ClinVar database, though Motelow cautioned that additional within-gene analyses are needed to ensure that this pattern holds across genes, and to rule out the possibility that all severe epilepsy variants are over-represented in the least mutation-tolerant genes in general. 

Nevertheless, from the results at hand, he and his abstract co-authors suggested that "sub-genic intolerance may help distinguish variants causing different epilepsy phenotypes and may provide additional diagnostic utility along with the discovery of the remaining genes associated with epilepsy."

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