Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant

Author:

Tvergaard Nicolai Kohring1,Tkemaladze Tinatin23,Stödberg Tommy45,Kvarnung Malin67,Tatton‐Brown Katrina8,Baralle Diana910,Tümer Zeynep111ORCID,Bayat Allan1121314

Affiliation:

1. Department of Clinical Genetics, Kennedy Center Copenhagen University Hospital Copenhagen Denmark

2. Department of Molecular and Medical Genetics Tbilisi State Medical University Tbilisi Georgia

3. Department of Pediatrics, Givi Zhvania Pediatric Academic Clinic Tbilisi State Medical University Tbilisi Georgia

4. Department of Women's and Children's Health Karolinska Institute Stockholm Sweden

5. Department of Pediatric Neurology Karolinska University Hospital Stockholm Sweden

6. Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

7. Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

8. St George's University Hospitals NHS Foundation Trust and St George's University of London London UK

9. Wessex Clinical Genetics Service, Princess Anne Hospital University Hospital Southampton NHS Foundation Trust Southampton UK

10. Faculty of Medicine University of Southampton, Duthie Building, Southampton General Hospital Southampton UK

11. Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen Kobenhavn Denmark

12. Department of Drug Design and Pharmacology University of Copenhagen Kobenhavn Denmark

13. Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Centre Dianalund Denmark

14. Department of Regional Health Research University of Southern Denmark Odense Denmark

Abstract

AbstractIonotropic glutamate receptors (iGluRs), specifically α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1‐4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss‐ or gain‐of‐function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep‐phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well‐established disease‐causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild–severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype.

Publisher

Wiley

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