Structural genomic variation in childhood epilepsies with complex phenotypes

Abstract

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

Diagnostic implications of genetic copy number variation in epilepsy plus

“…Most published reports are single‐center studies. The largest sample size was 2454 patients including a large cohort of 1366 patients with genetic generalized epilepsy in addition to 281 patients with rolandic epilepsy and 807 patients with adult focal epilepsy; the biggest cohort specifically addressing the epilepsy plus phenotype studied 222 individuals . The maximum frequency of pathogenic CNVs reported in any of these series was 12%, with a range of 5%‐12%.…”

“…However, CNVs may be seen in healthy control individuals, and determination of the pathogenicity of newly identified CNVs can be challenging. To evaluate the role of pathogenic CNVs and identify possible candidate genes, we investigated the occurrence of CNVs in epilepsy plus, in a cohort among the largest reported to date . Data were collected from eight centers and included both adults and children.…”

“…Samples with a total number of deletion or duplication (or both) calls >2 SD from the mean number of any calls/sample across the entire dataset were excluded from the analysis. Further manual analysis used a bespoke workflow based on current understanding of classification, including the American College of Medical Genetics guidelines and additional literature . CNVs were classified into four groups: pathogenic, possibly pathogenic, benign, or of unknown significance.…”

“…Current estimates suggest that genetics contribute to causation in 50%‐70% of the epilepsies . Copy number variations (CNVs) represent a prominent type of variant carrying risk for certain epilepsies . Whole genome oligonucleotide array CGH or SNP array is routinely included in evaluation of patients with complex phenotypes with a suspected genetic cause .…”

“…Whole genome oligonucleotide array CGH or SNP array is routinely included in evaluation of patients with complex phenotypes with a suspected genetic cause . CNVs, as a risk factor or cause, have been reported in ~5%‐12% of patients with different types of epilepsies . The risk of a pathogenic CNV is reportedly increased with concurrent intellectual disability (ID), dysmorphic features, autism spectrum disorder (ASD), drug resistance, or other comorbidities, from a study of 222 patients .…”