For the first time, the human genome is surveyed for rare variants associated with disease in an hypothesis-free manner, paving the way for genome-wide CNV association studies.

In addition to previously known genes, the authors identify CNVs associated with ubiquitin pathways.  Even though this paper carries the notion of “genome-wide investigation” in its title, this study was not about identifying common variants, but only rare-disease associated CNVs.

Ingo

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Helbig, I. Genome-wide CNV analysis in Autism. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

This paper demonstrates that overexpression of CACNA1G using a transgenic mouse model results in spike-wave discharges and absence seizures, indicating that enhancement of T-type calcium currents is sufficient for the generation of absence seizures.

The authors demonstrate that CACNA1G mediated currents are both necessary sufficient for the generation of absence seizures.  Genetic ablation of this gene actually makes mice resistent against spike-wave discharges when introduced into other mouse models.

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Helbig, I. CACNA1G overexpression induces spike-wave discharges. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

PCDH19 is the gene for EFMR (Epilepsy and mental retardation limited to females), a familial X-linked epilepsy which only affects females.  This paper describes mutations in PCDH19 in patients with a phenotype resembling Dravet syndrome.

It will be interesting to see whether mutations in PCDH19 can be identified in a significant subset of patients with Dravet syndrome negative for SCN1A mutations. Ingo

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Helbig, I. PCDH19 mutations in Dravet-like syndrome. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

The role of CLCN2 mutations in IGE remains questionable. This paper by Saint-Martin et al. describes two novel CLCN2 variants in Idiopathic Generalised Epilepsy and show that the variation has functional effects on channel function.

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Helbig, I. The return of CLCN2. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

This paper by Itsara et al. investigates the importance of large copy number variations in human population, showing that large deletions are generally rare and probably deleterious. A meta-analysis of published studies further highlights several genomic hotspots as candidate genes for human genomic disorders.

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Helbig, I. Large deletions and hotspots in human disease. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

The genetics of Benign Rolandic Epilepsy (BRE) is complicated and now genetic variants predisposing to BRE have been discovered to date. This study now shows association of the BRE phenotype and phenotype of centrotemporal spikes (CTS) with an intronic SNP in ELP4 (Elongator Protein Complex 4) in a genome-wide linkage scan and subsequent confirmation in a small association study.

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Helbig, I. BRE and association with ELP4. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

HCN2 is a top candidate gene for absence epilepsy, in fact there are few genes that are higher on the list of candidates than HCN2, which is expressed in the thalamus, modulating thalamocortical oscillations.  The problem is that mutations in humans have not been described to date, an orphan candidate gene in a way…

This paper presents another line of evidence for the involvement of HCN2 in absence epilepsy. A spontaneous mouse mutant -apathetic- was found to have a 4 base pair insertion in the coding region of HCN2.  Ingo

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Helbig, I. HCN2 goes apathetic. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

This paper is featured since it deals with the basics of epilepsy genetics – investigating whether a phenotype has a genetic contribution by looking at familial aggregation.  The authors investigate patients with neuro-cysticercosis and do not find evidence for familial aggregation.

Whereas the methodology is straightforward, it remains unclear what effect the authors could exclude.  For example, one would not expect a large degree of familial aggregation in herpes simplex encephalitis, but mutations in TLR3 and UNC-93B can be identified in some patients.

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Helbig, I. The genetics of seizures in neurocysticercosis. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

This gene continues to be a mystery.  An epilepsy gene not expressed in neurons with no obvious link to ion channels.

EFHC1 is one of the few genes found in human epilepsies that has been replicated in several studies.  The predominant phenotype of patients carrying EFHC1 variant is Juvenile Myoclonic Epilepy, where also familial inheritance is observed.  However, EFHC1 mutations have also been found in cases of other IGE subtypes and cryptogenic Temporal Lobe Epilepsy (TLE).

Suzuki et al. now report on their findings in EFHC1-deficient mice. The animals develop spontaneous myoclonus and are susceptible to seizures.  Interestingly, the authors find that EFHC1 is not expressed in neuron, but only in the choroid plexus and postnatal ependymal cilia.  In addition, GABAergic neurons are not affected.

The question remains how EFHC1 can lead to an idiopathic epilepsy phenotype that is assumed to be a disease of ion channels. Or maybe not?

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Helbig, I. EFHC1-deficient mice develop myoclonic seizures. Retrieved [enter date], from http://www.euroepinomics.wordpress.com

SV2A variants and variants in related genes are not associated with the response to Levetiracetam in a sufficiently large cohort.

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Helbig, I. Response to LEV and lack of SV2A variants. Retrieved [enter date], from http://www.euroepinomics.wordpress.com