GABRB3, 15q dups, and CNVs from exomes

GABAergic. Let’s start out with a provocative statement. There is a single gene that may explain more cases of Lennox-Gastaut Syndrome (LGS) and Infantile Spasms (IS) than you would expect, rivalling SCN1A for the most common gene found in this group of patients. It’s a gene that you are probably aware of but that you may think to be a very rare finding. In a recent publication in Annals of Neurology, the Epi4K consortium published their recent analysis of copy number variations that were derived from exome data. Combining de novo mutations and copy number variations points to GABRB3 as a major player in LGS and IS, explaining probably more than 2% of patients. Let’s find out about the twilight zone, strategies to obtain structural variants from exomes, and the re-emergence of the 15q duplication syndrome. Continue reading

Salt matters – SIK1 in epileptic encephalopathies

Inducible. Next generation sequencing technologies have the tremendous potential to identify disease-causing genes in a hypothesis-free manner. In a recent publication in the American Journal of Human Genetics, mutations in the gene for the salt-inducible kinase 1 (SIK1) are found in patients with early onset epileptic encephalopathy. In addition to a previously unknown functional network related to intracellular salt in the CNS, the authors demonstrate a peculiar mutational mechanism – activating truncation mutations. Continue reading

Of angels and interneurons

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