RELN. Amongst the various genes implicated in neurodevelopmental disorders, Reelin (RELN) has always been one of the more controversial genes. While bi-allelic variants have been implicated in lissencephaly with cerebellar hypoplasia, the role of autosomal dominant variants has been controversial and is currently considered disputed. Reelin is a relatively large gene – accordingly, missense variants are frequent. However, a recent study suggests that the picture might be more complicated and that both monoallelic and bi-allelic variant in Reelin may contribute to neurodevelopmental disorders. Here are my thoughts. Continue reading
Tag Archives: lissencephaly
Reelin, migration and an unexpected gene for lateral temporal lobe epilepsy
Reeler. In 1951, the geneticist D.S. Falconer identified a spontaneous mouse mutant with an abnormal, “reeling” gait. This mouse, aptly called reeler, was later found to have developmental abnormalities of the cerebellum and, most prominently, an inversion of the layers of the cortex. At this point, interest was piqued to identify the underlying gene, which was eventually pinpointed in 1995. Reelin, the culprit gene, was found to be a secreted protein of cortical support cells and was subsequently found to be the cause of human lissencephaly with cerebellar hypoplasia (LCH). In a recent study in the American Journal of Human Genetics, reelin takes on a new role as a novel gene for a familial form of lateral temporal lobe epilepsy. Continue reading
The ARX problem – how an epilepsy gene escapes exome sequencing
Silence. You might wonder why you hear very little about ARX in exome studies these days. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Mutations in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, it’s on the differential list for patients with Infantile Spasms without a known cause. Let me tell you about the problems that the ARX gene poses for exome sequencing. Continue reading
Microcephaly, WDR62, and how to analyze recessive epilepsy families
Success rate. What is in an exome? There are lots of rare and unknown variants that are hard to make sense of unless we can ask a specific question or have further data to limit the number of genes that we look at. Genetic studies in recessive diseases with limited candidate genes to consider might represent one of the most straightforward cases. In a recent paper in BMC Neurology, the genetic cause of a recessive epilepsy/intellectual disability syndrome in a consanguineous family presenting with primary microcephaly was solved using a single exome of an affected individual. Was this just lucky or can this strategy be applied to any recessive family with a reasonable chance? Continue reading
