Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy.
De novo mutations in the SCN1A gene, encoding the alpha1-subunit of the neuronal voltage-gated sodium channel Nav1.1, are the most frequent genetic cause of Severe Myoclonic Epilepsy of Infancy known so far. A few mutations inherited from an asymptomatic or mildly affected parent have been reported, suggesting that expression of the mutated gene may be variable in the transmitting parent. In this study, we report two unrelated families in which two children of unaffected parents had deleterious SCN1A mutations, and show evidence of somatic and germline mosaicism in the transmitting parents. In one of these families, direct sequencing of blood cell DNA was not sufficient to the SCN1A mutation in the transmitting asymptomatic parent who was mosaic for the mutation. We therefore developed a real-time PCR assay to selectively amplify and quantify the mutant allele present at low levels in the transmitting parent in both families. The allele-specific PCR technique used in this study will be of use in detecting other such cases. These findings will have major consequences for the genetic counseling of asymptomatic parents with only one affected child.
Depienne
Christel
C
INSERM U679 (formerly U289), Groupe Hospitalier Pitié-Salpêtrière, Paris, France. depienne@ccr.jussieu.fr
Arzimanoglou
Alexis
A
Trouillard
Oriane
O
Fedirko
Estelle
E
Baulac
Stéphanie
S
Saint-Martin
Cécile
C
Ruberg
Merle
M
Dravet
Charlotte
C
Nabbout
Rima
R
Baulac
Michel
M
Gourfinkel-An
Isabelle
I
LeGuern
Eric
E
D000328:Adult; D004252:DNA Mutational Analysis; D006239:Haplotypes; D006801:Humans; D007223:Infant; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D015222:Sodium Channels / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels