NMDA receptors and brain malformations: GRIN1-associated polymicrogyria

Ion channels and brain malformations. When the “channelopathy” concept first emerged – the idea that dysfunction of neuronal ion channels leads to neurological disease including epilepsy – it seemed implausible that such dysfunction could lead to malformations of cortical development. However, recent research has suggested that ion channel dysfunction may indeed be linked with brain malformations. In 2017, we saw convincing evidence that germline de novo variants in GRIN2B can cause malformations of cortical development. Some suggestive, but less conclusive, evidence has also linked SCN1A and SCN2A to brain malformations. Now Fry and collaborators demonstrate that de novo pathogenic variants in GRIN1 can also cause significant polymicrogyria, expanding the phenotypic spectrum of GRIN1-related disorders. As a disclaimer, I am also a co-author on the publication by Fry and collaborators. Continue reading

Speech dyspraxia and dysarthria – the other side of GRIN2A

GRIN2A. Mutations in several genes coding for NMDA receptor subunits have recently been found in various neurodevelopmental disorders. Amongst the different genes, GRIN2A is one of the most prominent ones and mutations in this gene are found in patients with epilepsy-aphasia syndromes. So far, we have mainly looked at GRIN2A from the epilepsy side. In a recent publication in Neurology, Turner and collaborators now examine the speech phenotype in GRIN2A families. They examine two families where speech issues are a prominent phenotypic feature. It turns out that GRIN2A mutations may predispose to a distinct speech phenotype. Continue reading

TADA – a joint analysis of de novo and inherited risk factors in autism

Beyond de novo. One of the most robust ways to interpret exome data is the analysis of de novo mutations. However, in addition to the 1-2 de novo events that we can identify in every individual, there is a plethora of inherited variants that often look suspicious. Unfortunately, other than looking at monogenic recessive disorders, we are often incapable of understanding the importance of these inherited variants and tend to ignore them. A recent publication in Nature now overcomes this difficulty by applying a joint analysis of inherited and de novo variants in autism. Continue reading

SETBP1, ZMYND11, and the power of joint exome and CNV analysis

Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. 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