Towards the identification of a genetic basis for Landau-Kleffner syndrome.
OBJECTIVE
To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.


METHODS
We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment.


RESULTS
A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2.


CONCLUSIONS
A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Department of Genetics, Children's University Hospital, Dublin, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Judith
J
Conroy
Paul A
PA
McGettigan
Dara
D
McCreary
Naisha
N
Shah
Kevin
K
Collins
Bronwyn
B
Parry-Fielder
Margaret
M
Moran
Donncha
D
Hanrahan
Thierry W
TW
Deonna
Christian M
CM
Korff
David
D
Webb
Sean
S
Ennis
Sally A
SA
Lynch
Mary D
MD
King
D000293:Adolescent; D000328:Adult; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002648:Child; D055028:Comparative Genomic Hybridization; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D018887:Landau-Kleffner Syndrome / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D036183:Receptor, EphB2 / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D036183:Receptor, EphB2; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C498440:BSN protein, human; C114729:NID2 protein, human; C586310:EPHB2 protein, human; C000717127:RELN protein, human
Candidate genes; Copy number variation; Discordant monozygotic twins; Exome sequencing; Rolandic epilepsy; Verbal auditory agnosia