Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.
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 ...
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