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.

Author Summary

Severe epilepsies associated with cognitive impairment in children are multifarious and most affected patients are sporadic cases. Thus, there is a challenge to identify which of these epilepsies are genetically determined, since their sporadic status excludes the use of classical genetic approaches. We have used microarrays, which are new technological tools to investigate the whole genome of an individual, to search for small genomic abnormalities and identify novel genes in 41 patients with a clinically well-characterized severe infantile epileptic disorder called Dravet syndrome. We have identified PCDH19, a new gene on chromosome X, which was recently found in a familial epileptic syndrome known as female-limited epilepsy and cognitive impairment. This gene was mutated in 12 out of 74 patients with clinical features compatible with Dravet syndrome. Eleven of these patients were females. The single male with a PCDH19 deficiency was mosaic in his skin; i.e., some of his cells express PCDH19 and others do not. This finding suggests that a new pathogenic mechanism—cellular interference—is associated with an unusual X-linked mode of inheritance in which females are more frequently affected than males.