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Abstract
Objectives: The aim of this study was to determine the genetic defect in a 4-generational family with an epileptic disorder characterized by febrile and afebrile polymorphic seizures and mild to severe mental retardation by means of analyzing the neuronal voltage-gated sodium channel α-subunit gene SCN1A for mutations.
Methods: A Bulgarian family was ascertained and clinically assessed, followed by mutation analysis of the SCN1A gene using direct sequencing to detect point mutations and multiplex amplicon quantification to identify copy number variations.
Results: A microdeletion encompassing the entire SCN1A gene segregating with all affected members was identified in this family. Additional analysis showed that the unaffected father of the proband is mosaic for the deletion. So far, SCN1A deletions, predicted to lead to haploinsufficiency, are exclusively identified in isolated patients with Dravet or contiguous gene syndromes. Because of the severe phenotype, SCN1A deletion carriers are usually not able to live independently and start a family, and hence do not transmit the disease.
Conclusions: We report an inherited SCN1A gene deletion not exclusively associated with Dravet syndrome. Moreover, our results demonstrate that SCN1A haploinsufficiency can cause a significant intrafamilial clinical variability including moderately affected to syndromal patients. The involvement of multiple genetic and environmental factors could be the basis of this difference in phenotype severity.
Footnotes
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Editorial, page 18
e-Pub ahead of print on May 19, 2010, at www.neurology.org.
*These authors contributed equally to this work.
Study funding: Supported by the Fund for Scientific Research Flanders (FWO-F), Methusalem Excellence Grant of the Flemish Government, and University of Antwerp. A.S. and L.D. are postdoctoral fellows of the University of Antwerp. L.R.F.C. is a postdoctoral fellow funded by the Fund for Scientific Research Flanders (FWO-F), Belgium.
Disclosure: The authors report no disclosures.
Received September 4, 2009. Accepted in final form February 10, 2010.
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