NaV1.2 Today is International SCN2A Day, 2/24/2023. SCN2A is on the long arm (q arm) of chromosome 2 at position 24.3, hence 2/24. In honor of this day, we wanted to refresh the SCN2A gene page, which was long overdue. Much has been learned since our initial post in 2015, so in addition to the gene page, here are three things to know about SCN2A in 2023.
1- Digitizing neurogenetics. Although our group has now been involved in phenotypic reconstructions for multiple neurodevelopmental genes, SCN2A will always hold a special place in this as this was our first formal foray into this in our 2021 publication by Crawford, Xian et al. By systematically collecting and phenotyping all individuals with SCN2A in the literature and from our internal cohort, we were able to outline the overall clinical landscape of SCN2A-related disorders and use this to better understand specific variant groups. This is a framework we have continued to draw on for other conditions, such as STXBP1.
2- Recurrent variants. At the time of our last gene page, there was some thought that recurrent variants such as p.R853Q were emerging. Not only have there now been over 60 recurrent variants described to date, many of these variants have been functionally characterized. Although there is certainly much to be learned still, these advances have elucidated key information on disease mechanisms of common disease-causing SCN2A variants.
3- Transcripts. The importance of transcript consideration is a recurring theme in neurogenetics this year, for example, in our recent DNM1 publication. SCN2A has both a neonatal and adult isoform, and this is especially important to pay attention to for two reasons – 1. There have been several reports of individuals with a variant that is only present in the neonatal isoform, and 2. Some variants associated with neonatal-onset epileptic encephalopathy exhibit greater dysfunction in the neonatal isoform than in the adult isoform, which is a potential disease-modifying target.
Here is what you need to know. In 2023, SCN2A-related disorders remain one of the most common causes of genetic epilepsies. With ongoing progress in understanding phenotypes and the consequences of specific variants through functional studies, SCN2A becomes increasing “trial-ready”. We hope that our knowledge will soon be translated in clinical trial and improvements in the care of individuals with SCN2A-related disorders.