Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Abstract

13Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and 14 revealed a role of rare deleterious variation in common epilepsies. To identify the shared and 15 distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole- 16 exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of 17 European ancestry. We focused on three phenotypic groups; the rare but severe developmental 18 and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized 19 epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, 20 individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in 21 constrained genes and in genes previously associated with epilepsy, with the strongest 22 enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA 23 receptor genes were enriched for missense variants across all three classes of epilepsy, while no 24 enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic 25 pathway or cation channels also showed a significant mutational burden in DEE and GGE. 26 Although no single gene surpassed exome-wide significance among individuals with GGE or 27 NAFE, highly constrained genes and genes encoding ion channels were among the top 28 associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and 29 GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare 30 epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for 31 GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date. 32 33 Epilepsy is a group of disorders characterized by repeated seizures due to excessive electrical 34 activity in the brain, one of the most common and burdensome neurological conditions worldwide 1; 35 2 . A core challenge for epilepsy genetics is identifying and disentangling the genetic architecture 36 and biological mechanisms underlying the variety of epilepsy types (e.g., focal vs. generalized) 37 and electroclinical syndromes. While the occurrence of epilepsy for many affected individuals 38 carries an underlying genetic component 3-5 , the highly heterogeneous nature of epileptic seizures, 39 epilepsy types, severity, and comorbidity makes it difficult to determine the specific genetic risks 40 for each patient. For individuals with common, complex types of epilepsy, where inheritance may 41 be due to strongly acting mutations, oligogenic or polygenic, the discovery of genetic risk factors 42 is particularly challenging. 43 Considerable progress in our understanding of the genetic risk factors for epilepsy has 44 been made in recent years thanks to the rapid growth and advancement in sequencing technology. 45 Dozens of epilepsy-causing genes have been identified in individuals diagnosed with severe 46 epilepsy syndromes 6-10 , known as the developmental and ...

2017 WONOEP appraisal: Studying epilepsy as a network disease using systems biology approaches

“…To date, several hundred loci have been annotated in humans and mice, 4 and more are being discovered daily. 7,8 However, because of these efforts, the genetic complexity of the epilepsies has also become clear. These approaches hold great promise for accelerating genetic stratification of patients for predicting outcomes and response to therapy.…”

“…6 The sequencing of novel variants is a highly advanced field. 7,8 However, because of these efforts, the genetic complexity of the epilepsies has also become clear. Clinical phenotypes associated with single mutations vary widely to expose a spectrum of outcomes.…”