How to find recessive disease genes for epileptic encephalopathies

The E2 story continues. There has been major progress in identifying the role of de novo mutations in infantile spasms and other epileptic encephalopathies. Over the last two years, more than 20 new genes for epileptic encephalopathies were discovered and we have good evidence suggesting that de novo mutations play a major role in these disorders. Moreover, we have gotten a good sense on how complicated it can be to call a de novo mutation pathogenic given the flood of rare genetic variants in the human genome. However, de novo mutations are not what we think about clinically when assessing a patient with new-onset epileptic encephalopathy. In a clinical setting, we are often concerned about underlying metabolic disorders, many of which are recessive. Accordingly, we felt that the next task of the E2 consortium was to assess the role of inherited variants in epileptic encephalopathies. Just to tell you in advance, it is not as easy as it sounds.

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Publications of the week – 15q13.3 deletions, POLG1 and liver failure, and twins

Update. In the last few weeks, we have tried to catch up with some recent publications in the field that mainly focused on autism spectrum disorder. This week’s publications, in contrast, cover a wide range of topics including the phenotypic spectrum of the 15q13.3 microdeletions, the importance of POLG1 in valproate-induced liver failure, and the most recent updates on epilepsy and twins. 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

The common variants in our genome that predispose to epilepsy – the ILAE GWAS

ILAE GWAS. This is one of the rare occasions when I can write on behalf of the ILAE Genetics Commission and discuss a recent publication. Earlier this week, the ILAE Consortium on complex epilepsies came online in Lancet Neurology. This study is a large meta-analysis of almost 9,000 patients and 26,000 controls looking at common genetic variants predisposing to common epilepsies, including the Idiopathic/Genetic Generalized Epilepsies and focal epilepsies. In a nutshell, when looking for common variants predisposing to the epilepsies, the answer is surprisingly simple. 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

Critical brain-expressed exons and de novo mutations in autism

Selection. De novo mutations in neurodevelopmental disorders including autism, schizophrenia, and intellectual disability raise an important question: are the mutations identified in patients pathogenic or are they simply genomic noise? A recent study in Nature Genetics tries to answer this question by looking at expression of particular exons in the brain and the overall mutational burden in these exons. They come up with critical exons, which seem to be particularly vulnerable in Autism Spectrum Disorder. Continue reading

Have we given up on the genetics of febrile seizures?

Fever, genes, and seizures. Undoubtedly, febrile seizures are the most common epilepsy syndrome in humans. Up to 5% of children have febrile seizures. In most children, these febrile seizures are self-limiting, and there is no recurrence. Usually, no long-term treatment is required. We know from family studies and twin studies that febrile seizures have a significant genetic component. Now here are two surprising facts: first, the genetic contribution to febrile seizures is entirely unknown. Secondly, to my knowledge, the genetic contribution to the most common epilepsy syndrome in man has not been addressed in any of the current large-scale studies. Let’s review why this is the case and why we should change this. Continue reading

Publications of the week – PRICKLE1, Phelan-McDermid syndrome, and mitochondrial genetics

The week in review. It’s currently a bit quiet in the literature with respect to novel gene findings. However, there is plenty to explore about genes and variants we already know and their role in human epilepsy. This week’s selection of publications is about functional studies in a gene for progressive myoclonus epilepsy, the EEG signature in a microdeletion syndrome, and contribution of mitochondrial genetics in intractable epilepsy. 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

Publications of the week: SLC13A5, SNAP25, and JME fMRI endophenotypes

Catching up. It has been a while since we posted a section on the recent publications in the field of epilepsy genetics. We are trying to catch up by briefly discussing three publications that appeared in the last two weeks. Here is what you should know about citrate transporters in epileptic encephalopathy, an STXBP1-interacting protein, and fMRI endophenotypes in Juvenile Myoclonic Epilepsy (JME). Continue reading