Genetic literacy. Sometimes important milestones don’t feel like much when you eventually reach them. Last Thursday, I woke up sleep-deprived after working on a grant all night and found an NCBI update in my mailbox. Primer Part 2 of the genetic literacy series of ILAE Genetics Commission was now published in Epilepsia and available on PubMed. Finally, both the introductory primers of the genetic literacy series are out – Part 1 dealing with the building blocks including general concepts of epilepsy genetics and epidemiology and now Part 2 about the paradigm shifts that were introduced with the advent of massive parallel sequencing. Both publications were revised and re-written over and over again to fit the overall didactic mission of the literacy series, an effort that takes approximately 10x as long as writing a typical review. But finally, as of May 10, 2018, both Primers are now in their final shape, published and open access to the international epilepsy community. And here is just a quick overview of what this paradigm shift is really about. Continue reading
Tag Archives: EFHC1
The microdeletion landscape of Genetic Generalized Epilepsy
CNV. Structural genomic variations or Copy Number Variations (CNVs) significantly contribute to the genetic architecture of many neurodevelopmental disorders. However, given the enormous variation in the human genome in healthy individuals, the precise contribution of CNVs remains poorly understood. In a recent publication in PLOS Genetics, we were able to assess the microdeletion architecture in more than 1,000 patients with Genetic Generalized Epilepsy (GGE) compared to more than 5,000 controls. We found that microdeletions occur almost twice as often in GGE patients compared to controls, an analysis that revealed both known suspects and interesting candidates. Continue reading
EFHC1 – retiring an epilepsy gene
The era of gene retirement. As of 2015, the list of epilepsy genes has shrunk by one. EFHC1, a gene initially proposed to be a monogenic cause of Juvenile Myoclonic Epilepsy, is no longer an epilepsy gene. A recent study in Epilepsia finds that EFHC1 variants initially thought to be pathogenic are found in unaffected controls of the same ancestry. Follow us on one of the most perplexing journeys that modern day neurogenetics has to offer, and the retirement of the first epilepsy gene. Continue reading
WWOX, spinocerebellar ataxia, neurodegeneration, and epilepsy
Exomes. Massive parallel sequencing technologies are ideally suited to identify the genetic basis of monogenic disorders, particularly recessive diseases. In a recent publication in the Orphanet Journal of Rare Disease, Abdel-Salam and collaborators identify a homozygous mutation in WWOX in a family with epileptic encephalopathy and neurodegeneration. Their study highlights the issues of how to interpret recessive gene findings spanning different phenotypes identified in the era of exome sequencing. Continue reading
The top three publications in epilepsy genetics 25 years ago
Looking back. In this week’s ILAE Genetics Commission post, we would like to look 25 years back and examine the most important publication in the field in 1989, the year the Berlin wall fell. What concepts did we have back then and how did our understanding of epilepsy and genes change? Here are the top three publications of 1989. Continue reading
Mutation intolerance – why some genes withstand mutations and others don’t
The river of genetic variants. The era of high-throughput sequencing has given us several unexpected insights into the human genome. One of these insights is the observation that mutations or variations can occur in parts of our genome without any major consequences. Every individual is a “knockout” for at least two genes in the human genome. This means that in every individual, both copies of a single gene are disrupted through mutations or small deletions or duplications. In addition, there are dozens, if not hundreds, of genes with disruptive mutations that affect only a single copy of the gene. Similar mutations in specific disease-associated genes, however, will invariably result in an early onset genetic disorder. This comparison already shows that the genes in the human genome differ with respect to the amount of disruptive genetic variation they can tolerate. A recent study in PLOS Genetics now tries to catalogue the genes in the human genome by assessing their mutation intolerance based on the genetic variation seen in large-scale exome datasets. Many genes for neurodevelopmental disorders are highly intolerant to mutations. Furthermore, some genes for monogenic epilepsies show surprising results in this assessment. Continue reading
How a pathogenic de novo mutation in SCN1A ended up in the Exome Variant Server
The omics flood. Large amounts of sequence data are produced every day and we can use the genetic information of several thousand individuals as controls of any present-day genetic study. However, much of research on “traditional” epilepsy genes had been performed prior to the genomic era and often only included limited control cohorts. This begs the question whether a closer look at the currently available data might provide additional information. Now, a recent paper in the Journal of Neurogenetics investigates the presence of reported mutations for epilepsy in large, available datasets. And the results are surprising. Continue reading
A new twist on an old gene: EFHC1 in epileptic encephalopathy
A peculiar gene. There is one gene in the small world of epilepsy genetics that has always troubled me. A gene that has an unknown function and is not expressed in the postnatal brain, but is well established as one of the few genes for autosomal dominant Juvenile Myoclonic Epilepsy (JME). This gene is EFHC1. Now, a recent paper in Epilepsia reports EFHC1 as a possible candidate gene in autosomal recessive epileptic encephalopathy with neonatal onset. The mystery surrounding this gene continues. Continue reading
