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.
The microdeletion story. The discovery of epilepsy-related microdeletions came as a surprise to the epilepsy community. While epileptologists had spent decades delineating the particular phenotypic features of the epilepsies in order to identify the underlying genes, the discovery of recurrent microdeletions upset our worldview. Recurrent microdeletions, arising from the duplication architecture of the human genome, were found to be associated with a broad range of neurodevelopmental disorders that were not previously considered to be connected. These disorders including autism, intellectual disability and schizophrenia were suddenly found to share parts of their genomic architecture with the IGE/GGE, an idiopathic epilepsy with little if no overlap. This overlap, which is not present for other epilepsies including the common focal epilepsies, is still unexplained.
Core or no core. Microdeletions also introduced us to the pains and perils of rare genetic variants and incomplete, if not paradoxical, segregation in families. In addition, while these variants were found to represent risk factors rather than classic monogenic factors, questions remained whether some phenotypes might be particularly typical of these variants. While claims of a possible core phenotype might be overly optimistic, some particular phenotypes might be more commonly seen with 15q13.3, 16p13.11 or 15q11.2 microdeletions. This question motivated Mullen and collaborators to assess the frequency of this microdeletion triad in patients with generalized epilepsy and intellectual disability.
The overlapping phenotypes. The combination of IGE/GGE and intellectual disability is rare, and the diagnosis of intellectual disability is sometimes considered an exclusion criterion for IGE/GGE. Accordingly, patients with overlapping phenotypes are typically not included in genetic studies. However, epilepsies with the characteristic features of IGE/GGE have been observed in microdeletion carriers with ID. In fact, this observation prompted the investigations of 15q13.3 microdeletions in IGE/GGE in the first place. In addition, particularly the 15q13.3 microdeletion may predispose to the rare combination of intellectual disability and typical absence epilepsy. In their recent study, Mullen and collaborators screened 60 patients with IGE/GGE and ID and found microdeletions at 15q13.3, 16p13.11 and 15q11.2 in 6/60 patients (10%). This is significantly higher than the cumulative 3% seen in patients with IGE/GGE only or any other microdeletion-related phenotype. Particularly the frequency of 15q13.3 microdeletions contributed to this increased burden of hotspot deletions seen in patients with IGE/GGE and ID, while the frequency of 16p13.11 and 15q11.2 microdeletions was not different. In addition to the finding by Mullen and collaborators that these patients were also found to have an increased risk for other microdeletions, this observation allows for interesting conclusions regarding the genetic architecture of neurodevelopmental disorders.
Architecture. Up to 6% of patients with IGE/GGE and ID carry 15q13.3 microdeletions. These microdeletions arise de novo in a significant proportion of patients, but may also be inherited. Within the spectrum of IGE/GGE phenotypes, absence epilepsies appear overrepresented including two patients with Early Onset Absence Epilepsy (EOAE) in the cohort analyzed by Mullen and collaborators. However, as seen in earlier studies, these variants have also been identified in patients with Juvenile Myoclonic Epilepsy (JME) without ID. Microdeletions at 15q11.2 and 16p13.11 have also been identified in other epilepsies such as Temporal Lobe Epilepsy, while 15q13.3 microdeletions are conspicuously absent. Collectively, this suggests that 15q13.3 microdeletions have a strong predominance for generalized epilepsies with intellectual disability and that milder phenotypes may be considered an incomplete presentation of an overlapping phenotype. While this observation may seem like semantics at first sight, it might have profound implications on how 15q13.3 microdeletion carriers may be counseled for the risk of particular phenotypes in their offspring.