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Exome sequencing identifies a de novo SCN 2 A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities
Author(s) -
Baasch AnnaLena,
Hüning Irina,
Gilissen Christian,
Klepper Joerg,
Veltman Joris A.,
GillessenKaesbach Gabriele,
Hoischen Alexander,
Lohmann Katja
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12554
Subject(s) - exome sequencing , missense mutation , hypotonia , epilepsy , intellectual disability , exome , phenotype , mutation , atrophy , genetics , channelopathy , medicine , disease gene identification , biology , bioinformatics , gene , neuroscience
Summary 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 SCN 2 A (c.5645 G > T ; p. R 1882 L ) gene encoding the α II ‐subunit of the voltage‐gated sodium channel N a v 1.2. A literature review revealed 33 different SCN 2 A 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 SCN 2 A 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 SCN 2 A mutations. Our own and literature data indicate that SCN 2 A ‐linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .