Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects

Abstract

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.

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

“…Recently we showed that genomic DNA methylation signatures also distinguished major FCD subtypes from TLE patients and non-epileptic controls [36]. Here, we confirmed and developmental, behavioral, and psychiatric problems (e.g., autism spectrum disorders, attention-deficit disorder, learning disabilities, schizophrenia), and seizures [14,24,48,52].…”

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

“…This number does not include the potentially toxic sSNVs in non‐coding parts of the genome that have also been linked to neurodevelopmental disorders such as autism (34, 38–43). Nor does it take into account the effect of somatic structural variants such CNVs that are known causes of focal epilepsies (44, 45). In other words, the contribution of somatic variants to focal epilepsies is likely more far‐reaching than what is known to date.…”

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

“…This manifold of diseases highlights the central role of genes on the long arm of chromosome 1 in overall development, but also brain structure and function. For example, recurrent rearrangements of 1q21.1 are associated with microcephaly or macrocephaly, developmental, behavioral, and psychiatric problems (e.g., autism spectrum disorders, attention-deficit disorder, learning disabilities, schizophrenia), and seizures [ 14 , 25 , 49 , 53 ]. 1q24 deletions cause a phenotype of intellectual disability, growth retardation, microcephaly, and facial dysmorphism [ 17 ].…”