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

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

Less is more – gene identification in epileptic encephalopathies through targeted resequencing

Exome no more. Over the last 15 months, we have repeatedly discussed how exome sequencing or genome sequencing is applied to neurodevelopmental disorders in order to discover new candidate genes and to assess the role of known candidate genes. We have also wondered sometimes whether exome sequencing is the most straightforward approach. Now – outpacing the two large international consortia using exome sequencing in epileptic encephalopathies – a recent study in Nature Genetics uses a different approach to uncover the genetic basis in 10% of patients with epileptic encephalopathies.  Targeted resequencing or gene panel analysis is a hybrid technology between candidate gene sequencing and next generation sequencing and focuses only on a subset of candidate genes. While their study provides a comprehensive overview over the genetics of rare epilepsy syndromes, it raises the question whether the era of large-scale exome sequencing is coming to a natural end. Continue reading

Exome sequencing in epileptic encephalopathies – the powers that be

The power, over and over again. I must admit that I am thoroughly confused by power calculations for rare genetic variants, particularly for de novo variants that are identified through trio exome sequencing. Carolien has recently written a post about the results we can expect from exome sequencing studies. For a current grant proposal, I have now tried to estimate the rate of de novos using a small simulation experiment. And I have realized that we need to re-think the concept of power. Continue reading

Copy numbers, seizures and speech

Why does this child with speech delay get an EEG? My first encounter with Landau-Kleffner-Syndrome and continuous spikes and waves during slow sleep (CSWS) was in medical school when my pediatric neurology attending faced me with this very question. I looked at him and basically had no idea. This is when I learned about the spectrum of rolandic epilepsies and how epilepsy interacts with speech. This concept is best explained by going back to the most common epilepsy in children, Benign Rolandic Epilepsy (BRE). And the genetics of BRE and the rolandic spectrum has been anything else but straightforward. Continue reading