A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2

Abstract

SUMMARYObjectives: Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far. Methods: Array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction (qPCR) were used to analyze the genomic status of a series of 47 unrelated RE patients who displayed various types of electroclinical manifestations. Results: Thirty rare CNVs were detected in 21 RE patients. Two CNVs were de novo, 12 were inherited, and 16 were of unknown inheritance. Each CNV was unique to one given patient, except for a 16p11.2 duplication found in two patients. The CNVs of highest interest comprised or disrupted strong candidate or confirmed genes for epileptic and other neurodevelopmental disorders, including BRWD3, GRIN2A, KCNC3, PRKCE, PRRT2, SHANK1, and TSPAN7. Significance: Patients with REs showed rare microdeletions and microduplications with high frequency and heterogeneity. Whereas only a subset of all genomic alterations found here may actually participate in the phenotype, the novel de novo events as well as several inherited CNVs contain or disrupt genes, some of which are likely to influence the emergence, the presentation, or the comorbidity of RE. The future screening of cohorts of larger size will help in detecting more de novo or recurrent events and in appreciating the possible enrichment of specific CNVs in patients with RE.

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses

“…Indeed, two genetic ‘hits’ are not an uncommon observation in RE. In our study, we identified four patients carrying two rare risk factor CNVs, Dimassi et al described 10/47 patients with two rare CNVs26 and Reinthaler et al 27 identified 1 patient with RE carrying two hotspot CNVs and 1 family with a de novo 16p11.2 duplication and an inherited DEPDC5 mutation. In a further study, one patient with RE was found to carry a de novo GABRG2 mutation as well as an inherited GRIN2A mutation, and a second a paternally inherited 15q11.2 duplication and a maternally inherited GABRG2 mutation.…”

“…The heterogeneous nature of RE is underpinned by our study, where only variation at Xp22.31 is recurrent. Out of the 30 rare CNVs identified in patients with RE by Dimassi, only two overlap with our larger cohort; we both identified one patient with a maternally inherited deletion of part of UNC13C , and we identified a de novo deletion of the 16p13.11 hotspot, whereas Dimassi identified a maternally inherited duplication of the same region 26. A heterogeneous mixture of CNVs has also been identified in a cohort of patients with LKS and CSWS17, which form the severe end of the epilepsy-aphasia spectrum, with RE at the mild end.…”

“…In a small study of 47 patients with either typical or EEG-atypical RE, half carried rare microdeletions and microduplications, some disrupting known causal genes for epilepsy. Two patients in this study with atypical RE also carried the 16p11.2 recurrent duplication 26. Motivated by this finding, Reinthaler et al undertook a screening of six recurrent CNVs in patients with typical RE and LKS/CSWS/atypical benign partial epilepsy ABPE 27.…”

Epilepsy genetics: The ongoing revolution

“…In contrast with RE, a genetic basis for LKS and CSWSS has long remained controversial [159]. The contribution of genetic factors in the pathogenesis of this spectrum of disorders was first suggested by aCGH and then confirmed by three recent parallel studies, which have led to the identification of CNV/mutations in GRIN2A, encoding the NMDA glutamate receptor subunit gene GluN2A, in most of the families reported as well as and in 5-10% of sporadic cases [160][161][162][163]. The recurrent 16p11.2 microduplication including PRRT2 was recently shown to be a risk factor for RE [162,164,165].…”

DEPDC5 does it all: Shared genetics for diverse epilepsy syndromes

“…The genetic revolution has extended to the more common, age-related focal epilepsy syndrome benign epilepsy with centrotemporal spikes (BECTS; also referred to as rolandic epilepsy), long known to be genetically mediated 9 but only more recently associated with specific genes. [10][11][12][13][14][15] In this issue of Annals of Neurology, we are presented with 2 articles describing an increasingly wide phenotypic spectrum associated with mutations in the gene DEPDC5 (disheveled, Egl-10 and pleckstrin domain containing protein 5). 16,17 The protein encoded by DEPDC5 was recently identified as a member of the GATOR1 complex that exerts an inhibitory effect on mammalian target of rapamycin (mTOR)-mediated processes, such as cell growth and proliferation.…”