De novo missense variant in the GTPase effector domain (GED) of DNM1L leads to static encephalopathy and seizures

Abstract

DNM1L encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of DNM1L have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of DNM1L (c.2072A>G, p.Tyr691Cys). Functional studies in Drosophila demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of DNM1L-related disorders.