title: Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.
abstract: 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.
authors.affiliation: Département de Génétique et Cytogénétique, AP-HP, Fédération de Génétique, Hôpital de la Salpêtrière, Paris, France. christel.depienne@upmc.fr
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouteiller
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cheuret
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Oriane
authors.initials: O
authors.lastname: Trouillard
authors.forename: Baya
authors.initials: B
authors.lastname: Benyahia
authors.forename: Chloé
authors.initials: C
authors.lastname: Quelin
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Sophie
authors.initials: S
authors.lastname: Julia
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Agnès
authors.initials: A
authors.lastname: Gautier
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.forename: Sophie
authors.initials: S
authors.lastname: Meyer
authors.forename: Patrick
authors.initials: P
authors.lastname: Berquin
authors.forename: Marie
authors.initials: M
authors.lastname: Hélias
authors.forename: Isabelle
authors.initials: I
authors.lastname: Py
authors.forename: Serge
authors.initials: S
authors.lastname: Rivera
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000091363:Protocadherins; D016415:Sequence Alignment; D012727:Sex Characteristics
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins