Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities
Article first published online: 1 MAR 2014
Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
Volume 55, Issue 4, pages e25–e29, April 2014
How to Cite
Epilepsia, 55(4):e25–e29, 2014
- Issue published online: 22 APR 2014
- Article first published online: 1 MAR 2014
- Manuscript Accepted: 6 JAN 2014
- Renate Maass foundation
- Intellectual disability;
- Sodium channel;
- Epileptic encephalopathy;
- Rett-like syndrome
Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII-subunit of the voltage-gated sodium channel Nav1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations.
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