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Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the  SCN1A  gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in  SCN1A . In order to identify new genes responsible for the disorder in the  SCN1A -negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the  PCDH19  gene, was found in one male patient. To confirm that  PCDH19  is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional  SCN1A -negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the  PCDH19  deletion. Patients with  PCDH19  and  SCN1A  mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with  PCDH19  mutations. These results suggest that  PCDH19  plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.

Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females