A genetic counselor’s wish list for epilepsy genetics in 2015

Mt. Rainier. After our recent posts about the 2014 AES in Seattle, we received an email from Beth in Boston, highlighting some of the issues that genetic counselor face in epilepsy genetics when dealing with next gen sequencing data. Beth drew up a wish list for 2015 and asked us for comments. Here is a brief discussion between Beth and me on how high throughput epilepsy genetics sometimes comes to grinding halt in clinical practice. Continue reading

These are the top 10 epilepsy genes of 2014

Top 10. 2014 has been a very productive year in epilepsy gene discovery and with our final blog post this year, we wanted to provide a brief overview of what has been pertinent this year. From the multitude of novel genes identified this year, here are the 10 most relevant findings – including some genes that you probably didn’t expect. Continue reading

Beyond the Ion Channel – and back

Where do all the ion channels come from? I would like to start off with a brief commentary about the current state of gene discovery in human epilepsy. Some of our readers rightfully took offense to my previous statement that gene discovery in epilepsy it over – quite the contrary is true, and I apologize for any confusion that I may have caused. Gene discovery in epilepsy is one of the few areas of human genetics with an ongoing, rapid sequence of gene discovery with a tremendous translational potential. But we also need to reconsider the name of this blog – we are far from being beyond the ion channel. The ion channel concept has made a remarkable return in human epilepsy genetics. Let’s find out why. Continue reading

Dynamin 1, the synapse, and why epilepsy gene discovery is now officially over

E2 consortium. Infantile Spasms and Lennox-Gastaut Syndrome are two epilepsy syndromes with a strong genetic component. De novo mutations play an important role in genetic epilepsies. However, given the overall mutational noise in the human genome, telling causative genes from innocent bystanders is difficult. In the largest and most comprehensive analysis so far, our E2 consortium just published a joint analysis of 356 patient-parent trios, which were analyzed by exome sequencing. In addition to implicating DNM1, GABBR2, FASN, and RYR3, this publication sends a clear message: the age of gene discovery in epilepsy is over – from now on, genes will find themselves. Let me tell you what I mean by this. Continue reading

The 1003 possible autism genes – a matter of constraint

Overview. There have been numerous publications on de novo mutations in autism and intellectual disability over the last three years. Many of these studies struggle to distinguish signal from noise, and the plethora of findings leaves the reader wondering which genes are bona fide autism genes and in which cases the evidence is limited. A recent paper in Nature Genetics uses a new metric to assess expected versus observed de novo mutations in more than published 1000 autism patient-parent trios – and the answers appear to be straightforward. Continue reading

Typical versus atypical: exome sequencing in pediatric epilepsies

Exome mining. Trio exome sequencing is both easy and difficult at the same time. If you manage to identify a plausible de novo mutation, the job is pretty much done. However, if no plausible de novo is found, things can become complex very quickly. Some of the known genes for recessive disorders are quite variable and therefore difficult to interpret. Also, we know little about the overall spectrum of the recessive disorders and the plausibility of atypical cases. A recent paper in Clinical Genetics takes a comprehensive approach to the genetic basis of pediatric epilepsies by exome sequencing. The authors include the analysis of recessive and compound heterozygous variants, and they follow up on some of the biomarkers that establish the diagnosis. There are some surprising findings. Continue reading

Publications of the week – SCN8A, CNTNAP4, EML1, and SCN1A

Catching up. This week’s review of recent publications might be relevant for you because it adds new pertinent details to known epilepsy genes and discusses novel gene findings that might be applicable in clinical practice. This post covers publications on SCN8A in epileptic encephalopathy, CNTNAP4 and interneurons, EML1 in brain malformations, and the meaning of SCN1A variants in small epilepsy families. Continue reading

The OMIM epileptic encephalopathy genes – a 2014 review

EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading