In:
Epilepsia, Wiley, Vol. 60, No. 4 ( 2019-04), p. 689-706
Abstract:
Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Type of Medium:
Online Resource
ISSN:
0013-9580
,
1528-1167
DOI:
10.1111/epi.2019.60.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2002194-X
