A polygenic trickle of rare disruptive variants in schizophrenia

Polygenic. Schizophrenia is a complex neurodevelopmental disorder that is assumed to be caused by a mixture of genetic and non-genetic factors. The genetic component in schizophrenia is thought to be polygenic, i.e. due to the interaction of multiple genetic factors. Rare variants may play a particular role in this presumable polygenic genetic architecture, but so far this component of the genetic morbidity has been hard to pin down. Now, a recent study in Nature explores the role of rare, disruptive mutations in schizophrenia using large-scale population-based exome sequencing. Let’s find out about a new level of exome-wide honesty and why even a gene with 10 disruptive mutations in cases and none in controls is only mentioned in passing. Continue reading

2B or not 2B – mutations in GRIN2B and Infantile Spasms

Year of the glutamate receptor. A few months ago we wrote a post about the triplet of Nature Genetics publications that established GRIN2A mutations as a cause of disorders within the epilepsy aphasia spectrum. GRIN2A codes for the NR2A subunit of the NMDA receptor, one of the most prominent neurotransmitter receptors in the Central Nervous System. Now, a recent paper in the Annals of Neurology reports mutations in the GRIN2B subunit as a cause of Infantile Spasms. Interestingly, the functional consequences of these mutations are completely different from GRIN2A-related epilepsies. Continue reading

GRIN2A encephalopathy, epilepsy-aphasia and rolandic spikes

The GRIN2A triple. The idiopathic focal epilepsies are a group of childhood seizure disorders ranging from mild, self-limiting rolandic epilepsy to severe epileptic encephalopathies. The EEG feature of sharp-slow waves originating from the rolandic region is the unifying feature. As the rolandic region is part of the brain regions involved in speech production, acquired aphasia, i.e. loss of speech, can be a prominent feature in some patients. A strong genetic contribution in idiopathic focal epilepsies is assumed, but the genes involved have remained largely elusive. Now, three back-to-back publications in Nature Genetics highlight a prominent role of GRIN2A, probably the most counter-intuitive epilepsy gene ever found. Continue reading