Clinical and Neurodevelopmental Characteristics of Paralogous Gain-of-Function Variants at GRIA2 p.Gly792 and GRIA3 p.Gly803

Abstract

GRIA-related disorders arise from disease-causing variants in GRIA1, GRIA2, GRIA3, or GRIA4 that encode α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs). Rare monoallelic GRIA1-4 variants affecting AMPAR function can potentially lead to neurodevelopmental disorders. The impact on AMPAR function may manifest as either gain-of-function (GOF) or loss-of-function (LOF). We recruited nine unrelated patients with either known disease-causing GOF variants in GRIA3 at position p.Gly803 or variants at the paralogous position in GRIA2 (p.Gly792). Specifically, five patients carried a de novo GRIA3 variant (p.Gly803Glu or p.Gly803Val), one carried a maternally inherited GRIA3 variant (p.Gly803Ala) and three carried de novo GRIA2 variants (p.Gly792Arg, p.Gly792Val, or p.Gly792Glu) which we demonstrate are also GOF. Recurrent symptoms included developmental delay affecting both motor skills and language abilities; cognitive impairment; behavioral and psychiatric comorbidities; hypertonia, cerebral palsy, non-epileptic myoclonus, and treatment-resistant epilepsy. We also provide insights into social skills, levels of autonomy, living arrangements, and educational attainment. We compared the clinical features associated with the two paralogous GOF GRIA2 and GRIA3 variants. Our study elucidates the developmental aspects, cognitive abilities, seizure profiles, and behavioral challenges associated with these variants and contributes to advancing our understanding and treatment of patients affected by this rare condition.

Keywords: AMPAR; epilepsy; natural history; neurology; syndrome.

FIGURE 1

GRIA2 variants slow glutamate unbinding from homomeric GluA2 AMPARs, suggesting increased affinity and gain‐of‐function. (A) Representative currents from wild‐type (WT) flip and flop GluA2(Q)/γ2 receptors jumped into 10 mM glutamate (black bars) from NBQX at −60 mV (in the presence of CTZ and PEPA, respectively, to block desensitization). In each case, the weighted time constant of current decay (τ_{w,Glu off}) is shown. Lower traces show corresponding records from the flip variant G792V and the flop variant G792E. The dashed lines indicate the original baseline current. (B) Swarmplots showing pooled values τ_{w,Glu off} for flip receptors (left) and flop receptors (right). Summary data (mean ± standard deviation) for each group are shown as gapped lines to the right of the raw data. Indicated p‐values indicate differences from respective WT controls.

FIGURE 2

Overview of neurological features in our cohort. The plot shows the features (grouped and colored by their broad type) and their occurrence (% of patients).

FIGURE 3

Overview of extra‐neurological features in our cohort. The plot shows the features (grouped and colored by their broad type) and their occurrence (% of patients).