Clinical and Neurodevelopmental Characteristics of Paralogous Gain‐of‐Function Variants at <scp> <i>GRIA2</i> </scp> p.Gly792 and <scp> <i>GRIA3</i> </scp> p.Gly803

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.

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Journal
Clinical Genetics
Published
2025-05-20
DOI
https://doi.org/10.1111/cge.14770
Citations
1
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
1.82

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article

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

Simona Orcesi, Maria Rosaria Iascone, Lamia Ben Jemâa, Mélanie Fradin et al.
1 citations
Clinical Genetics
Genetics and Neurodevelopmental Disorders
1.82
article

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

Simona Orcesi, Maria Rosaria Iascone, Lamia Ben Jemâa, Mélanie Fradin, Davide Tonduti, Thomas Besnard, Thouraya Ben Younes, Elisabeth Stoltz Sjöström, Dorota Studniarczyk, Ian D. Coombs, Sylvia Napuri, Gaëtan Lesca, Christèle Dubourg, Allan Bayat, Stuart Cull-Candy, Vincent Cruz, Mark Farrant, Jennifer Friedman, Wallid Deb, Sandra Mercier, Rebekka S. Dahl, Miriam Essid, Heng Wang, X L Dou, Sana Karoui
article en
1 citations

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.

Clinical GeneticsVol. 108(5)
Université Claude Bernard Lyon 1 (FR), Tunis University (TN), University of Copenhagen (DK), Centre National de la Recherche Scientifique (FR), Children’s Institute (US), Inserm (FR), University of Southern Denmark (DK), University of Milan (IT), University of Pavia (IT), University of California San Diego (US), Center For Children With Special Needs (US), Hospices Civils de Lyon (FR), Hôpital Mongi Slim (TN), Ospedale Papa Giovanni XXIII (IT), Institut NeuroMyoGène (FR), Institut de génétique et de développement de Rennes (FR), Institut du Thorax (FR), Centre Hospitalier Universitaire de Rennes (FR), National Institute of Neurology Mongi-Ben Hamida (TN), University College London (GB), Université de Rennes (FR), Tunis El Manar University (TN), Nantes Université (FR)
European Commission, Novo Nordisk, Novo Nordisk Fonden, Medical Research Council
Quality Education
Openalex Percentile: Top 16%
Genetics and Neurodevelopmental Disorders
1.82
DOIOpen Access PDFOpenAlex
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