GRIN2A – this is what you need to know in 2015

GRIN2A. Mutations in GRIN2A have initially been described in patients with neurodevelopmental disorders of diverse severity, including seizures, in 2010. In 2013, its prominent role in idiopathic focal epilepsies (IFE) was discovered simultaneously by three groups (Carvill 2013, Lemke 2013, Lesca 2013) and since that, mutations have repeatedly been associated with this spectrum of disorders. Continue reading

Robinsoe Crusoe, NFXL1, and speech delay

Founder variant. Specific language impairment (SLI) is a common neurodevelopmental disorder, presenting as delays in acquiring language skills in children who have no hearing loss or other developmental delays. There is a strong genetic component, but the genetic architecture of SLI is entirely unknown. In a recent publication in PLOS Genetics, exome sequencing is performed in the founder population of the Robinson Crusoe Island where SLI is common. Using a combination of exome sequencing and association study, the autors identify a variant In NFXL1 as a plausible candidate for language delay. 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

ESES and the postsynapse – CNKSR2 in genetic epilepsies

Structure. Despite tremendous advances in understanding its genetic underpinnings in the last few years, electrical status epilepticus during slow-wave sleep (ESES) is a poorly understood neurodevelopmental disorder and to a certain extent the prototype of an epileptic encephalopathy. Slow-wave sleep in affected children is entirely replaced by epileptiform activity, leading to significant neurocognitive impairment with an emphasis on speech impairment. In a recent publication in Annals of Neurology, alterations in CNKSR2 are identified in families with a more severe course of ESES, highlighting the postsynapse as a possible player in ESES pathogenesis. Continue reading

Beyond the Ion Channel – and back

Where do all the ion channels come from? I would like to start off with a brief commentary about the current state of gene discovery in human epilepsy. Some of our readers rightfully took offense to my previous statement that gene discovery in epilepsy it over – quite the contrary is true, and I apologize for any confusion that I may have caused. Gene discovery in epilepsy is one of the few areas of human genetics with an ongoing, rapid sequence of gene discovery with a tremendous translational potential. But we also need to reconsider the name of this blog – we are far from being beyond the ion channel. The ion channel concept has made a remarkable return in human epilepsy genetics. Let’s find out why. Continue reading

The 1003 possible autism genes – a matter of constraint

Overview. There have been numerous publications on de novo mutations in autism and intellectual disability over the last three years. Many of these studies struggle to distinguish signal from noise, and the plethora of findings leaves the reader wondering which genes are bona fide autism genes and in which cases the evidence is limited. A recent paper in Nature Genetics uses a new metric to assess expected versus observed de novo mutations in more than published 1000 autism patient-parent trios – and the answers appear to be straightforward. Continue reading

Surrendering to genomic noise – de novo mutations in schizophrenia

Heterogeneity. Family-based exome sequencing or trio exome sequencing for de novo mutations is currently the method of choice to identify genetic risk factors in neurodevelopmental disorders. However, given the increasingly recognized variability in the human genome, the hunt for causative de novo mutations is sometimes an uphill battle – it is impossible to distinguish causal mutations from random events unless genes are affected repeatedly. In a recent publication in Nature, Fromer and colleagues present the most comprehensive search for de novo mutations in schizophrenia to date. They observe an incredible genetic heterogeneity that reflects the genetic architecture of neurodevelopmental disorders. 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