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.

Analysis of SCN1A mutation and parental origin in patients with Dravet syndrome

“…There were still 14 DS patients with no SCN1A mutations in our study, other genes such as SCN9A and PCDH19 may be involved in the pathogenesis of DS. 19,20 Our next step is to carry out SCN9A and PCDH19 mutation analysis in these patients. There were various types of SCN1A mutations including missense, nonsense, splice-site and frame-shift mutations caused by base substitutions, deletions or insertions.…”

Pitfalls in genetic testing: the story of missed SCN1A mutations

“…It should however be noted that despite the clear genotype–phenotype correlation between SCN1A mutations and DS, mutations in several other genes have also been associated with a DS phenotype (Depienne et al. 2009b; Carvill et al. 2014; Nava et al.…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…Men who are hemizygous for PCDH19 mutations have a normal cognitive level and no epilepsy. Cellular interference has been proposed to explain the discrepancy between the clinical manifestations of heterozygous girls and hemizygous boys [84,87]. This model suggests that for a pathological phenotype to occur an individual must have two distinct populations of protocadherin cells (mutated and nonmutated).…”