Abstract Details

Title Mutations in DEPDC5 cause Familial Focal Epilepsy with Variable Foci and are a common cause of familial non-lesional focal epilepsy

Topic Epilepsy

Presentation(s) (-)

Poster/Presentation
Number 012

Objective

Background FFEVF is characterized by seizures arising from different cortical regions in different affected family members. Brain imaging is normal. Seizure onset varies from infancy to adult life. Affected individuals occasionally have neuropsychiatric co-morbidities. Linkage studies mapped FFEVF to chromosome 22q12, but the causative gene had so far eluded identification.

Design/Methods We applied exome sequencing to two FFEVF families previously linked to chromosome 22q12, identifying DEPDC5 as the most likely candidate gene. We sequenced DEPDC5 in six additional 22q12-linked families and scanned DEPDC5 for sequence variation in 82 unrelated probands from families with at least two individuals with non-lesional focal epilepsy. We used qRT-PCR, immunofluorescence and western blot analysis to study DEPDC5 expression and subcellular localization.

Results Heterozygous mutations in DEPDC5 were identified in 7/8 FFEVF families linked to chromosome 22q12 and in 10/82 (12.2%) probands from the small families with focal epilepsy. Each DEPDC5 mutation segregated with the FFEVF phenotype in the respective family and was absent in both dbSNP135 and an in-house exome sequencing database of 710 chromosomes. Most mutations caused premature termination codons suggesting haploinsufficiency as pathogenic mechanism. DEPDC5 encodes a1604 amino acid protein of unknown function, probably implicated in modulation of intracellular signaling. Mouse Depdc5 transcripts were detected at low levels in all brain regions and throughout brain development. Immunofluorescence analyses in mouse and human brain showed specific expression in neurons and perinuclear localization.

Conclusions Our findings establish DEPDC5 mutations as the most common known cause of familial focal epilepsy and identify a novel pathogenic pathway for epilepsy.

Authors/Disclosures
Massimo Pandolfo, MD, FAAN (Montreal Neurological Institute/Hospital)	Dr. Pandolfo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Design Therapeutics . Dr. Pandolfo has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Pandolfo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Solid Bio. Dr. Pandolfo has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurocrine. Dr. Pandolfo has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Design Therapeutics. Dr. Pandolfo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Larimar. Dr. Pandolfo has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics. Dr. Pandolfo has stock in Voyager Therapeutics. The institution of Dr. Pandolfo has received research support from Freidreich Ataxaia Research Alliance. Dr. Pandolfo has a non-compensated relationship as a Scientific Advisory Board with Friedreich Ataxia Research Alliance that is relevant to AAN interests or activities. Dr. Pandolfo has a non-compensated relationship as a Member-Meeting Management Committee with AAN that is relevant to AAN interests or activities.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
James T. Hughes, FRACP (Northwest Neurology)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Denis S. Crimmins, MBBS, FRACP	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Francois Dubeau, MD (Montreal Neurological Hospital and Institute)	Dr. Dubeau has nothing to disclose.
	No disclosure on file
	No disclosure on file
Patrick Cossette, MD (CHUM)	No disclosure on file
	No disclosure on file
	No disclosure on file
Jose M. Serratosa, MD, PhD (Unidad De Epilepsia/Servicio De Neurologia)	No disclosure on file
	No disclosure on file
Frederick Andermann, MD, FRCPC, FAAN	No disclosure on file
Eva Andermann, MD, PhD (Montreal Neurological Inst)	No disclosure on file
	No disclosure on file
Samuel F. Berkovic, MD, FRACP (Epilepsy Research Centre)	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��