Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing

Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading

Sequencing for developmental disorders on a national level – the DDD(UK) study

DDD. It’s probably the most impressive of all exome sequencing studies of 2014 and I almost missed it. Late December last year, the Deciphering Developmental Disorders study was published in Nature, reporting the genetic findings in more than 1,000 patient-parent trios, which were collected in a systematic nation-wide approach in the United Kingdom and Ireland. The analysis of more than 1,600 de novo mutations in this cohort provides another fascinating view into the genetics of neurodevelopmental disorders, independently confirming the role of DNM1 and pointing out several genes that act through either activating or dominant-negative mutations. Let me guide you through a study that comes to the sobering conclusion that even entire nations are too small to understand the genetics of neurodevelopmental disease. Continue reading

ESES and the postsynapse – CNKSR2 in genetic epilepsies

Structure. Despite tremendous advances in understanding its genetic underpinnings in the last few years, electrical status epilepticus during slow-wave sleep (ESES) is a poorly understood neurodevelopmental disorder and to a certain extent the prototype of an epileptic encephalopathy. Slow-wave sleep in affected children is entirely replaced by epileptiform activity, leading to significant neurocognitive impairment with an emphasis on speech impairment. In a recent publication in Annals of Neurology, alterations in CNKSR2 are identified in families with a more severe course of ESES, highlighting the postsynapse as a possible player in ESES pathogenesis. Continue reading

Publications of the week – SRP9, Nebulin, and Kuf’s disease

Issue 2/2015. For the second issue of our publications of the week in 2015, we have selected recent publications on the genetics of Febrile Seizures, the complexities of interpreting variants in large genes and functional studies on progressive myoclonus epilepsies due to mutations in SCARB2 and CTSF. Continue reading

SCN8A encephalopathy – and how it differs from Dravet Syndrome

Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading

AP4S1 in fever-associated epilepsies and spastic paraplegia

Peds vs. adult. Sometimes it makes a fundamental difference in diagnosis whether a patient is seen in a pediatric setting or by an adult specialist later in life. Here is the most recent example from our consortium, which was just published in Human Molecular Genetics: what initially looked like recessive inheritance with intellectual disability and a peculiar fever-associated epilepsy syndrome eventually turned out to be the second reported family of the novel spastic paraplegia gene AP4S1. This raises the question of how much we are missing if we are looking at the wrong point in time. Let’s have a look at how genetics can help us see an overlap of diseases where we usually don’t have a chance to. Continue reading

TADA – a joint analysis of de novo and inherited risk factors in autism

Beyond de novo. One of the most robust ways to interpret exome data is the analysis of de novo mutations. However, in addition to the 1-2 de novo events that we can identify in every individual, there is a plethora of inherited variants that often look suspicious. Unfortunately, other than looking at monogenic recessive disorders, we are often incapable of understanding the importance of these inherited variants and tend to ignore them. A recent publication in Nature now overcomes this difficulty by applying a joint analysis of inherited and de novo variants in autism. Continue reading

A question of conformation – chemical correction of LGI1 dysfunction

ADTLE. Autosomal Lateral Temporal Lobe Epilepsy is a rare monogenic epilepsy that has epileptic seizures with auditory auras as the most impressive feature. This condition is caused in LGI1. In contrast to most other autosomal dominant epilepsies, LGI1 is not an ion channel, but a secreted protein that binds to synaptic cell adhesion proteins. Therefore, the function of LGI1 has always remained slightly mysterious. In a recent publication in Nature Medicine, the functional properties of two LGI1 mutations are modelled in mice. Allowing neurons to secrete altered LGI1 protein otherwise targeted for degradation helped recover some of LGI1’s function. 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