LAUSR

A Recurrent EIF2AK2 Missense Variant Causes Autosomal-Dominant Isolated Dystonia Thomas Musacchio, MD, Michael Zech, MD , Martin M. Reich, MD, Juliane Winkelmann, MD,2,3,4,5‡ and Jens Volkmann, MD1‡ We read with interest the article by Kuipers and colleagues, reporting the identification of an EIF2AK2 c.388G > A (p.Gly130Arg) missense variant in 9 individuals with dystonia from 3 families. Although bioinformatics algorithms almost universally predicted a benign impact of the variant, the authors demonstrated complete co-segregation of c.388G > A (p.Gly130Arg) in 7 affected subjects from the index family and its de novo occurrence in another pedigree. Moreover, the authors were able to elucidate abnormally increased activation of EIF2AK2 in c.388G > A (p.Gly130Arg)harboring patient cells, consistent with a gain-of-function effect. Notably, a set of de novo EIF2AK2 missense variants affecting amino-acid positions other than glycine-130 have been described as causative for a neurodevelopmental syndrome with leukoencephalopathy, developmental delay, and episodic neurologic regression (Fig A). In an attempt to replicate the association between the EIF2AK2 c.388G > A (p.Gly130Arg) variant and dystonic presentations, we re-analyzed whole-exome sequencing data from 953 patients with various forms of dystonia. We identified EIF2AK2 c.388G > A (p.Gly130Arg) in 1 German kindred for which exome-sequences of 3 affected subjects had been generated, but no mutations in previously