Clinical and functional characterization of GRIA-related disorders: translating genetic diagnostics into personalized treatment

Targeted gene(s)/phenotype:

GRIA1 (#138248), GRIA2 (#618917), GRIA3 (#300699), and GRIA4 (#617864)

 

Summary (1000 letters max):

GRIA genes encode AMPAR receptors which are important for the function of excitatory neurons. Disease-causing variants in GRIA, GRIA2, GRIA3, and GRIA4 cause a neurodevelopmental disorder (NDD) with mild-profound developmental and cognitive impairment, behavioral difficulties, early-onset and treatment-resistant seizures. Only few patients have been reported leaving phenotypical spectrum and genotype-phenotype correlations ill-defined.

We want to:

  1. collect clinical data from patients with rare GRIAvariants in order to establish a database of high-quality genetic and clinical data sets.
  2. Systematically evaluate the impact of GRIAvariants on key parameters of AMPAR function using a combination of biochemical and functional assays and advanced electrophysiology to pinpoint exact phenotypical mutational impact on AMPAR molecular function and classify pathogenicity of variants.
  3. Analyze correlations between patient disease phenotypes and specific effects on receptor function to establish genotype-phenotype patterns and perform pilot experiments to explore options for rescue pharmacology using existing AMPAR drugs.

 

Coordinating clinician: Allan Bayat

Institution: Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark

Contact email: abaya@filadelfia.dk, bayabayabayat@hotmail.com   



Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples: No
  • Resampling of patients: No
  • Linked to a translational/basic research project: Yes