Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability

Abstract

IMPORTANCECopy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability.OBJECTIVES To evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability. DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures.MAIN OUTCOMES AND MEASURES DNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient's phenotype. RESULTSOf the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty-three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation: ABAT, KIAA2022, COL4A1, CACNA1C, and SMARCA2. ABAT duplication was associated with Lennox-Gastaut syndrome and KIAA2022 deletion with Jeavons syndrome. CONCLUSIONS AND RELEVANCEThe high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes.

Diagnostic implications of genetic copy number variation in epilepsy plus

“…This number reaches 12.7% when we also consider the possibly pathogenic CNVs. Previous similar studies report a diagnostic yield ranging from ~5% to 12% . Thus, our result fits at the upper limit of this range, probably mainly due to the “epilepsy plus” phenotype of our cohort and to the application of a standardized workflow.…”

“…Thus, our result fits at the upper limit of this range, probably mainly due to the “epilepsy plus” phenotype of our cohort and to the application of a standardized workflow. Previously published studies that reported similar yields of pathogenic CNVs (9.3%, 8.1%, and 12%, respectively) also examined patients with complex epilepsy including ID. Overall, results from both our and similar previous studies indicate that within the complex phenotype of neurodevelopmental disorders, when seizures are associated with ID or with other neurological and nonneurological comorbidities, there is a higher probability of identifying a pathogenic CNV than in epilepsy alone.…”

“…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 .…”

“…6 CNVs, as a risk factor or cause, have been reported in ~5%-12% of patients with different types of epilepsies. 2,4,5,[7][8][9] 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. 10 Recurrent CNV "hotspots" predispose to different types of epilepsies.…”

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

“…Diagnostic yields are usually greater for gene panels and WES than CMA . Copy number variants diagnosed through CMA may identify an etiology in 5%‐16% of patients investigated, whereas gene panels and/or WES tend to have a higher yield, elucidating an underlying diagnosis in 25%‐40% of cases …”