Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

• Published in: BMC medical genetics 2016-04, Vol.17 (1), p.34, Article 34
• Main Authors: Fry, Andrew E, Rees, Elliott, Thompson, Rose, Mantripragada, Kiran, Blake, Penny, Jones, Glyn, Morgan, Sian, Jose, Sian, Mugalaasi, Hood, Archer, Hayley, McCann, Emma, Clarke, Angus, Taylor, Clare, Davies, Sally, Gibbon, Frances, Te Water Naude, Johann, Hartley, Louise, Thomas, Gareth, White, Catharine, Natarajan, Jaya, Thomas, Rhys H, Drew, Cheney, Chung, Seo-Kyung, Rees, Mark I, Holmans, Peter, Owen, Michael J, Kirov, George, Pilz, Daniela T, Kerr, Michael P
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age of Onset; Autism; Brain research; Care and treatment; Child; Child, Preschool; Comparative Genomic Hybridization; Consortia; Copy number variations; DNA Copy Number Variations; Epilepsy; Epilepsy - genetics; Epilepsy in children; Families & family life; Female; Genes; Genetic aspects; Genetic Predisposition to Disease; Genomes; Humans; Intellectual disabilities; Intellectual Disability - genetics; Male; Mental retardation; Middle Aged; Mutation; NAV1.1 Voltage-Gated Sodium Channel - genetics; Patients; Polymorphism, Single Nucleotide; Risk factors; Segregation; Sequence Deletion; Single nucleotide polymorphisms; Studies; Wales; Young Adult
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-016-0294-2

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.