Molecular characteristics

Two homozygous truncating mutations in the RUSC2 gene (R866X and R1318X), ARG866TER and ARG1318TER, respectively have been reported. A homozygous c.2596C-T transition (c.2596C-T, NM_0148063) in the RUSC2 gene in two siblings, resulting in an arg866-to-ter (R866X) substitution proximal to the RUN domain that interacts with RAB proteins. Another homozygous c.3952C-T transition (c.3952C-T, NM_014806.3) in the RUSC2 gene in an unrelated subject, resulting in an arg1318-to-ter (R1318X) substitution distal to the RUN domain that interacts with RAB proteins. This was confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations would impair RUSC2 function and disrupt intracellular trafficking and synaptic vesicular transport, resulting in impaired synaptogenesis, neuronal dysfunction, and intellectual disability. Proximal mutation to the RUN domain would result in a complete loss of function and more severe phenotype. Diagnosis can be made by whole exome sequencing and targeted gene analysis in suspected cases.