Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.
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.
Depienne
Christel
C
Département de Génétique et Cytogénétique, AP-HP, Fédération de Génétique, Hôpital de la Salpêtrière, Paris, France. christel.depienne@upmc.fr
Bouteiller
Delphine
D
Keren
Boris
B
Cheuret
Emmanuel
E
Poirier
Karine
K
Trouillard
Oriane
O
Benyahia
Baya
B
Quelin
Chloé
C
Carpentier
Wassila
W
Julia
Sophie
S
Afenjar
Alexandra
A
Gautier
Agnès
A
Rivier
François
F
Meyer
Sophie
S
Berquin
Patrick
P
Hélias
Marie
M
Py
Isabelle
I
Rivera
Serge
S
Bahi-Buisson
Nadia
N
Gourfinkel-An
Isabelle
I
Cazeneuve
Cécile
C
Ruberg
Merle
M
Brice
Alexis
A
Nabbout
Rima
R
Leguern
Eric
E
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
D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins