Architecture. Even though we often write about novel gene findings in the epilepsies, we assume that most epilepsies are complex genetic or polygenic. Polygenic inheritance suggests the genetic architecture is composed of multiple interacting genetic risk factors, each contributing a small proportion to the disease risk. However, when using the phrase genetic architecture, sometimes I am not quite sure what I actually mean by this. For example, how many genes are needed? This is why I wanted to build a model genetic architecture and explore what happens if we build a genetic disease solely from rare risk variants. Follow me to a brief back-of-the-envelope calculation of how this might work.
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