Isolates. Last week, the FinnGen biobank went live, and Nature dedicated an entire issue to the launch of this initiative. In brief, FinnGen is a large Finnish research project providing genomic and clinical data from a Finnish biobank with the aim to provide new insights into human disease. Finland is an isolated population, which offers unique insights into the role of rare variants in disease. When I checked the FinnGen database for association with SCN1A, I was surprised that three missense variants have been associated with various diseases. Here is what a founder population can tell us about the various roles of SCN1A in human disease. Continue reading
FASTA, FASTQ, SAM, BAM, BWA, GC, GATK, IGV. Phew. Day 2 at the EuroEPINOMICS bioinformatics workshop in Leuven. Usually my work starts after the initial NGS raw data quality control and mapping procedures. Today’s topics are supposed to improve my understanding of sequencing analysis and NGS data interpretation. While we are still struggling, other scientists have done their home work already. Here are some of the remarkable publications from this week.
In final week before our EuroEPINOMICS bioinformatics workshop in Leuven people get a little busy and start reading up on all sorts of things. Accordingly, this week’s papers come from all areas of genetics and life science, including three studies in Annals of Neurology on epilepsy genetics.
Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading
A productive week in epilepsy genetics. Scientists and editors were certainly busy this week reporting novel variants and deletions as well the experimental and statistical advances for their interpretation.
A de novo GRIN2A missense mutation in early-onset epileptic encephalopathy. We and others have associated variants affecting the GRIN2A gene with a range of childhood focal epilepsy syndromes. Continue reading
Desert Dessert. Cold temperatures, streets closed because of snow – this is not what you expect when traveling to Israel. You also do not expect to have the chance to taste traditional Bedouin food and to see a beautiful canyon every morning. The biggest surprise is that you do not expect this during a workshop. From Dec 12-15th, the European epilepsy genetic community gathered in Be’er Sheva and Sde Boker, Israel for a combined epilepsy genetics workshop and a Young Researcher Meeting. This is a brief attempt to capture the atmosphere of this workshop for everybody who could not attend. By the way, “desert dessert” is a port wine produced in the Negev desert.
Genetic mirage. We look at genetic variants all the time. There are few genetic variants that stare back at us. 15q11.2 is one these variants, facing us with the constant question how we define and perceive genetic risk. Not because of its pathogenicity, but because of the confusion that it causes. Continue reading
Angelman Syndrome and UBE3A. Angelman Syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, typical facial features and a usually happy demeanor. Patients with Angelman Syndrome usually do not acquire active speech and often show a characteristic, atactic gait. Also, patients with Angelman Syndrome have a characteristic EEG pattern and many children have seizures. Angelman Syndrome is a genetic disorder due to loss of function of UBE3A, a ubiquitin ligase expressed in the CNS. Ubiquitin ligases are the bin collectors of the cell. By attaching ubiquitin to proteins, proteins are labelled for cellular degradation. How a malfunction of a cellular garbage truck causes such a complex neurodevelopmental disorder is poorly understood. A recent study, however, points out an important role for interneurons…. Continue reading
Crompton and colleagues recently published the clinical and genetic description of a large family with Familial Adult Myoclonic Epilepsy (FAME). This phenotype is particularly interesting since it provides some insight into how neurologists conceptualize twitches and jerks. It is also a good example that large families do not necessarily result in a narrow linkage region, particularly when centromeric regions are involved.
What is myoclonus? Despite usually mentioned in the context of epilepsy, most people are inherently familiar with myoclonus. Most of us “twitch” when we fall asleep and sometimes experience this twitch as part of a dream. These episodes are entirely normal and are called hypnic jerks, but they give people a good idea of what a sudden, brief, shocklike, involuntary movement caused by muscular contraction or inhibition would feel like. Myoclonus in the setting of epilepsy is usually mentioned as part of a Juvenile Myoclonic Epilepsy (JME) or Progressive Myoclonus Epilepsy (PME). Please note that both epilepsies use different endings to describe the twitch (“-us” vs. “–ic”). This is mainly convention. Basically, myoclonus is a brief shock-like twitch, which can affect almost every part of the body and can be due to dysfunctions in various regions in the Central Nervous System.
The neuroanatomy of twitching. A motor command from the cerebral cortex has to pass through several steps prior to execution. For example, the simple command of tapping a finger on the table surface is prepared by the cortex through several loops before being sent down your spine. Accordingly, myoclonus can arise from different parts in the brain. (1) The cortical myoclonus is due to a purely cortical source and can be seen in many forms of symptomatic myoclonus. (2) The cortico-subcortical myoclonus is due to feedback from the cortex to other brain areas. This is the myoclonus we see in patients with JME. Both variants may be seen on EEG since the cortex is involved. (3) The subcortical-supraspinal myoclonus is generated in the brain stem or below and is responsible for phenomena such as hyperekplexia or startle disease. Some forms of hyperekplexia, literally “exaggerated surprise”, are due to mutations in genes involved in glycinergic transmission and can be found in some isolated communities such as the Jumping Frenchmen of Maine. (4) Finally, there is also spinal and peripheral myoclonus.
FAME – epilepsy or movement disorder? Familial Adult Myoclonic Epilepsy (FAME) is an enigmatic familial disorder with the triad of myoclonus, tremor and seizures. Several families have been described and two loci on 8q23.3-8q24.11 and 2p11.1-q212.2 for FAME have been established. The underlying genes are still unknown. Crompton and colleagues no describe a large six-generation family with FAME in Australia/New Zealand. The familial disease usually starts with tremor in early adulthood in the affected family members, even though a wide range of age of onset is observed. Interestingly, only a quarter of all affected family members had seizures, which is in contrast to previous studies. Therefore, FAME may actually be better characterized as a movement disorder with concomitant seizures rather than a familial epilepsy syndrome. The authors also point out the difficulties distinguishing FAME from the much more common essential tremor (ET). In particular, the well-described response to β-blockers seen in patients with ET can also be observed in some family members.
The genetics of FAME. Crossovers during meiosis usually lead to a progressive narrowing of the linkage interval in familial disorders. However, the lack of crossover events leads to very large linkage intervals even in very extended families. The family described by Crompton et al. links to the pericentromeric region of chromosome 2. Pericentromeric regions usually have a low frequency of crossover events, and this phenomenon has also delayed the identification of other familial epilepsies such as Benign Familial Infantile Seizures with mutations in PRRT2. The linkage region contains almost 100 genes and Figure 1 shows the “candidate gene landscape” in this region. While some genes clearly classify as top candidate genes, the majority of the genes in this region are unknown in the context of epilepsy. Therefore, identification of the FAME gene will be exciting and provide us with novel insight on how genetic alterations may produce combined neurological phenotypes.
Exomes on Twitter. Two different trains of thoughts eventually prompted me to write this post. First, a report of a father identifying the mutation responsible for his son’s disease pretty much dominated the exome-related twittersphere. In Hunting down my son’s killer, Matt Might describes his family’s journey that finally led to the identification of the gene coding for N-Glycanase 1 as the cause of his son’s disease, West Syndrome with associated features such as liver problems. The exome sequencing that finally led to the discovery was part of a larger program on identifying the genetic basis of unknown, putatively genetic disorders reported in a paper by Anna Need and colleagues, which is available through open access. This paper is an interesting proof-of-principle study that exome sequencing is ready for prime time. Need and colleagues suggest exome sequencing can find causal mutations in up to 50% of patients. By the way, a gene also that turned up again was SCN2A in a patient with severe intellectual disability, developmental delay, infantile spasms, hypotonia and minor dysmorphisms. This represents a novel SCN2A-related phenotype, expanding the spectrum to severe epileptic encephalopathies.
The exome consult. My second experience last week was my first “exome consult”. A colleague asked me to look at a gene list of a patient to see whether any of the genes identified (there were 300+ genes) might be related to the patient’s epilepsy phenotype. Since I wasn’t sure how to best handle this, I tried to run an automated PubMed search for combination of 20 search terms with a small R script I wrote. Nothing really convincing came up except the realisation that this will be an issue that we will be increasingly faced in the future: working our way through exome dataset after the first “flush” of data analysis did not reveal convincing results. Two terms that came to my mind were bioinformatic literacy as something that we need to improve and Program or be Programmed, a book by Douglas Rushkoff on the “Ten commands of the Digital Age”. In his book, he basically points out that in the future, understanding rather than simply using IT will be crucial.
The cost of interpretation is rising. The Genome Center in Nijmegen suggests on their homepage that by the year 2020, whole-genome sequencing will be a standard tool in medical research. What this webpage does not say is that by 2020, 95% of the effort will not go into the technical aspects of data generation, but into data interpretation. For biotechnology, interpretation will be the largest marketing sector.
So, what about epilepsy? “50% of cases to be identified” sounds good for any grant proposal that I would write, but this might be a clear overestimate. Need and colleagues used a highly selected patient population and even in the variants they identified, causality is sometimes difficult to assess. We are maybe much further away from clinical exome sequencing in the epilepsies than we would like to admit. The only reference point we have for seizure disorders to date is large datasets for patients with autism and intellectual disability. While some genes with overlapping phenotypes can be identified, we would virtually be drowning in exome data without being capable of making sense of this.
10,000 exomes now. I would like to predict that after having identified some low-hanging fruits with monogenic disorders, 10,000 or more “epilepsy exomes” would have to be collected before making significant progress. It is, therefore, crucial not to be tempted by wishful thinking that particular epilepsy subtypes necessarily have to be monogenic, as in the case of epileptic encephalopathies or other severe epilepsies. Much of the genetic architecture of the epilepsies might be more complex than anticipated, requiring larger cohorts and unanticipated perseverance.