Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females

Abstract

Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation. © 2010 Wiley-Liss, Inc.

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

“…Extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies, meaning that genotype-phenotype correlations are not always straightforward. The same gene and even the same mutation can lead to broad phenotypic variations, and the same epilepsy syndrome can be caused by mutations in different genes [Depienne et al, 2011;Marini et al, 2011;Carvill et al, 2014;Goldberg-Stern et al, 2014;Møller et al, 2015]. This illustrates the insufficiency of the previous single gene test approach and the need for a multigene next-generation sequencing (NGS)-based strategy, either as full-genome sequencing, WES, or targeted gene panels.…”

Epilepsy Caused by Pcdh19 Gene Mutation: A Review of Literature and the Authors’ Observations

“…При обоих заболеваниях лихорадка явля-ется основным провоцирующим фактором приступов [1,3,5]. В связи с тем, что два заболевания имеют об-щие клинические признаки, рекомендуется исследо-вание на мутацию PCDH19 у пациентов с клиникой синдрома Драве и отрицательным результатом анали-за на мутацию SCN1A [7].…”

“…У обеих наших больных, как и в описанных в ли-тературе случаях, лихорадка являлась триггерным фактором развития приступов [5,18]. У пациентки А. судороги развивались на фоне каждого острого вирус-ного заболевания.…”

Fever-induced seizures: where are we today?

“…Dok je dio djevojčica urednog kognitivnog razvoja, mnoge imaju psihomotorni zastoj u razvoju s elementima pervazivnog razvojnog poremećaja. Sama bolest nastaje zbog mutacije gene za protocadherin 19, PCDH19, i slijedi neuobičaje-no X-vezano nasljeđivanje s poštedom muškog spola 37 . Muškarci su normalni nezahvaćeni preno- znanica.…”