Chromosome 15q11-13: one region, many disorders

Cytogenetics. 15q11-13 can be an intimidating region, even for many seasoned genetics professionals. Several factors contribute to this, including a complex genomic architecture, genomic imprinting, an acrocentric chromosome, and several genes critical to neurological function. For today’s blog post, we’ll try to unravel some of its complexity to make interpretation of copy number variants (CNVs) in this area clearer.

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Identifying the Doose gene – SLC6A1 mutations in Myoclonic Astatic Epilepsy

Doose Syndrome. In the early 1970s, a group of children with severe childhood epilepsies was found to have comparable clinical features that consisted of quick jerks and subsequent drop attacks amongst other types of epileptic seizures. These seizures, myoclonic-astatic or myoclonic-atonic seizures, eventually became the defining feature of an epilepsy syndrome referred to as Myoclonic Astatic Epilepsy or Doose Syndrome. In the recent issue of the American Journal of Human Genetics, we report on the first true gene for Doose Syndrome. Here is the story of SLC6A1 (GAT-1). Continue reading

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

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

2013 in review: top three lists and the gene finding of the year

Gene of the year. Let’s take a minute to look back at the very busy year of 2013. There were major advances in many areas of epilepsy genetics. First and foremost, massive (and I mean massive) progress has been made in the genetics of the epileptic encephalopathies, where de novo mutations have been identified as a major source of genetic morbidity. Secondly, the new technologies have made it possible to identify several novel genes for various epilepsy types. Out of these genes, we have again selected the most important finding in 2013. And the gene finding of the year is… Continue reading

Beneath the surface – the role of small inherited CNVs in autism

Grey zone. Structural genomic variants or copy number variations (CNV) can be reliably assessed using array comparative genomic hybridization (array CGH) or Single Nucleotide Polymorphism (SNP) arrays.  However, for deletions or duplications smaller than 50-100 kB, these technologies have a poor detection rate with many false positive and false negative findings unless platforms are used that target specific candidate regions. Exome analysis, on the other hand, is capable of assessing genetic variation reliably on the single base-pair level. Between both technologies, there is a grey zone of structural genomic variants that are difficult to detect; CNVs smaller than 50 kB are often difficult to assess, and the extent and pathogenic role of these small CNVs is unclear. Now, a recent paper in the American Journal of Human Genetics manages to detect small CNVs through exome data. Their analysis in patients with autism, parents, and unaffected siblings suggests a contribution of small inherited CNVs to the overall autism risk. Continue reading

Identifying core phenotypes – epilepsy, ID and recurrent microdeletions

Triad. There are three microdeletions in particular that increase the risk for the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE). This triad includes microdeletions at 15q13.3, 16p13.11 and 15q11.2, which are hotspot deletions arising from the particular architecture of the human genome. While the association of these microdeletions with epilepsy and other neurodevelopmental disorders including autism, intellectual disability and schizophrenia is well established, the core phenotype of these variants remains elusive, including the question whether such a core phenotype actually exists. In a recent paper in Neurology, Mullen and collaborators zoom in on a possible core phenotype of these microdeletions. The authors investigate a phenotype in which these microdeletions are particularly enriched: generalized epilepsy with intellectual disability. Continue reading

16p13.11 microdeletions and the male bias

The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable.   Continue reading

How human evolution has shaped epilepsy genes

Man and ape. Comparative genomics is relating the differences between species in the genome to the phenotype. When the first comparisons between human and chimpanzee were published in 2005, neuroscientists were  excited that this comparison would show what makes our brain human. A glance at the genes clusters that rapidly evolved during human-specific evolution was sobering. Many of the genes that rapidly evolved are immune-regulatory genes, highlighting  our constant struggle with some parasites, bacteria and viruses and our arrangement with the microbiome, the cloud of microbes contribute ten times as many cells to our bodies than we do. Prominent genes such as FOXP2, a gene found to be disrupted in patients with developmental language problems, and most other brain genes barely show up as a group in comparative genomics.

Segmental duplications and human evolution. Recent human evolution did not only leave traces at the single-base pair level that allows for the discovery of individual sequence differences but also larger structural genomic variants including segmental duplications. Recurrent microdeletions such as the 15q13.3, 16p13.11 or 15q11.2 microdeletions occur relatively frequently because the genomic sequence of these deletions is located between segmental duplications (Figure 1). These segmental duplications are so similar that the DNA replication machinery sometimes mistakes one duplication for the other (e.g. the “right flanking duplication” for the “left flanking duplication”). Thereby, the intervening sequence is either deleted or duplicated. Segmental duplications are relatively human-specific, for example a paralogue region for the 15q13.3 microdeletion is not present in rodents. Even in chimpanzees, the segmental duplications that give rise to Prader-Willi-Syndrome, Williams-Syndrome or Spinal Muscular Atrophy are not present, indicating that something very human-specific must have happened here that resulted in these segmental duplications, which give rise to so-called genomic disorders. While many of the epilepsy genes identified through family studies including SCN1A or GABRG2 are conserved in animals, microdeletions are not.

Figure 1. The human genome is a complicated meshwork of duplications and deletions that are lineage-specific, i.e. only occuring in human. One example of this is the genetic architecture of human chromosome 16. When comparing baboon and man, the human chromosome 16 is a complicated puzzle of deletions, duplication, duplications-within-duplications etc. This is the reason why there are at least five different microdeletions syndromes on chromosome 16, resulting from accidental genomic rearrangements between these duplications. This image is modified from a figure on the web page of the Eichler lab.

The SRGAP2 story. Two recent publications on the SRGAP2 gene illustrate the problems with reasoning around the human-specific changes. Saitsu and colleagues describe a female patient with epileptic encephalopathy and a balanced translocation in SRGAP2, a  gene highly expressed in the developing forebrain. Balanced translocations are very rare  and might provide insight into monogenic epilepsy syndromes. The function of SRGAP2 is still unknown. The second paper by Dennis and collaborators describes the evolution of the SRGAP2 family, hypothesizing that the evolution paralleled neocortical expansion at the transition of Australopithecus to Homo.

How human is our SRGAP2?  While the suggestion that disruption of a human-specific gene results in West Syndrome carries some appeal, comes with an almost philosophical flaw. Epileptic encephalopathy, a severe neurodevelopmental disease, may be conceptualized as a disruption of basic cellular or network processes, e.g. large malformations, neurometabolic disorders or fundamental disruptions of synaptic function rather than defects in the subtle differences between man and ape that make us human. In fact, the Toronto Database of Genomic Variants lists several intragenic deletions and duplications in SRGAP2, suggesting that disruptions of this gene may be seen in apparently healthy individuals. Possibly, the genetic architure in SRGAP2 might predispose to deletions, duplications or more complicated rearrangements that even result in balanced translocations. Evolution has merely generated a complex human-specific gene prone to recombination events rather than a genuine epilepsy gene.

Evolutionary genomics and EuroEPINOMICS. So-called hotspot microdeletions including variants at 15q13.3, 16p13.11, 15q11.2 are the immediate result of recent genomic changes that allowed us to be human. Segmental duplications rather than changes on the base-pair level might have been the main driver for human evolution, and the occurence of microdeletions may be conceptualized as a “trade-off” for the fragile human genomic architecture. Microdeletions already help us explain approximately 3% of cases of epilepsy. It can be hypothesized that similar effects on a smaller genomic level are still to be discovered and may help explain additional genetic findings seen in epilepsy patients.