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The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel  de novo  mosaic p.(Gly126Arg)  SHANK1  variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox–Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy.  In silico  analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein–protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the “non-canonical” binding of Rap1.

Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant