Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.
Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy.



We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation.



8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort.



We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK. andrew.fry2@wales.nhs.uk.|Institute of Cancer and Genetics, Cardiff University, Cardiff, CF14 4XN, UK. andrew.fry2@wales.nhs.uk.
Andrew E
AE
Fry
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
Elliott
E
Rees
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
Rose
R
Thompson
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
Kiran
K
Mantripragada
Llwyneryr Unit, Learning Disability Services, Clasemont Road, Morriston, Swansea, SA6 6AH, UK.
Penny
P
Blake
Learning Disabilities Directorate, Abertawe Bro Morgannwg University NHS Trust, Treseder Way, Caerau, Cardiff, CF5 5WF, UK.
Glyn
G
Jones
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Sian
S
Morgan
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Sian
S
Jose
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Hood
H
Mugalaasi
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Hayley
H
Archer
Department of Clinical Genetics, Glan Clwyd Hospital, Betsi Cadwaladr University Health Board, Rhyl, Denbighshire, LL18 5UJ, UK.
Emma
E
McCann
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.|Institute of Cancer and Genetics, Cardiff University, Cardiff, CF14 4XN, UK.
Angus
A
Clarke
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Clare
C
Taylor
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Sally
S
Davies
Department of Paediatric Neurology, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Frances
F
Gibbon
Department of Paediatric Neurology, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Johann
J
Te Water Naude
Department of Paediatric Neurology, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Louise
L
Hartley
Department of Paediatric Neurology, Morriston Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, SA6 6NL, UK.
Gareth
G
Thomas
Department of Paediatric Neurology, Morriston Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, SA6 6NL, UK.
Catharine
C
White
Department of Paediatrics, Royal Glamorgan Hospital, Cwm Taf University Health Board, Pontyclun, Mid Glamorgan, CF72 8XR, UK.
Jaya
J
Natarajan
Welsh Epilepsy Centre, Neurosciences Directorate, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Rhys H
RH
Thomas
Neurology and Molecular Neuroscience Research, Institute of Life Science, College of Medicine, Swansea University, Swansea, SA2 8PP, UK.
Cheney
C
Drew
Neurology and Molecular Neuroscience Research, Institute of Life Science, College of Medicine, Swansea University, Swansea, SA2 8PP, UK.
Seo-Kyung
SK
Chung
Neurology and Molecular Neuroscience Research, Institute of Life Science, College of Medicine, Swansea University, Swansea, SA2 8PP, UK.
Mark I
MI
Rees
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
Peter
P
Holmans
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
Michael J
MJ
Owen
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.
George
G
Kirov
Institute of Medial Genetics, University Hospital of Wales, Cardiff, CF14 4XW, UK.
Daniela T
DT
Pilz
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, CF24 4HQ, UK.|Learning Disabilities Directorate, Abertawe Bro Morgannwg University NHS Trust, Treseder Way, Caerau, Cardiff, CF5 5WF, UK.
Michael P
MP
Kerr
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D014852:Wales; D055815:Young Adult
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
Array comparative genomic hybridization; Copy number variation; Epilepsy; Intellectual disability; SCN1A