Autism and mild epilepsy associated with a de novo missense pathogenic variant in the GTPase effector domain of DNM1

Abstract

Dynamin 1 is a GTPase protein involved in synaptic vesicle fission, which facilitates the exocytosis of neurotransmitters necessary for normal signaling. Pathogenic variants in the DNM1 gene are associated with intractable epilepsy, often manifested as infantile spasms at onset, developmental delay, and a movement disorder, and are located in the GTPase and middle domains of the protein. We describe a 36-year-old man with autism and moderate intellectual disability who experienced only a few generalized seizures between the age 16 and 30 years. Using a whole sequencing approach, we identified the c.1994T>C p.(Leu665Pro) de novo novel missense pathogenic variant in the GTPase effector domain (GED) of the DNM1 protein. Structural analyses suggest that this substitution impairs both the stalk formation and its interactions, known to be important for the dynamin-1 physiological cellular function. Our data expand the spectrum of phenotypes associated with pathogenic variants in the DNM1 gene, linking a variant in the GED domain with autism and onset in the adolescence of mild epilepsy, a phenotypic presentation remarkably different from the early infantile epileptic encephalopathy associated with pathogenic variants in the GTPase or middle domains.

Keywords: DNM1; GTPase effector domain; autism; epilepsy; exome sequencing; mutation.