Analysis of rare copy number variation in absence epilepsies.
OBJECTIVE
To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum.


METHODS
We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE).


RESULTS
We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes.


CONCLUSIONS
Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Laura
L
Addis
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Richard E
RE
Rosch
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Antonio
A
Valentin
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Andrew
A
Makoff
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Robert
R
Robinson
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Kate V
KV
Everett
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Lina
L
Nashef
Department of Basic and Clinical Neuroscience (L.A., R.E.R., A.V., A.M., D.K.P.), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Neuroscience Discovery Research (L.A.), Eli Lilly and Company, Erl Wood, Surrey, United Kingdom; Wellcome Trust Centre for Neuroimaging (R.E.R.), Institute of Neurology, University College London, United Kingdom; Department of Clinical Neurophysiology (A.V.), Department of Neurology (L.N.), and Department of Child Health (D.K.P.), King's College Hospital, United Kingdom; Department of Paediatric Neurology (R.R.), Great Ormond Street Hospital, London, United Kingdom; and St George's University of London (K.V.E.), Cranmer Terrace, London, United Kingdom.
Deb K
DK
Pal