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

Nicolai Kohring Tvergaard*, Tinatin Tkemaladze, Tommy Stödberg, Malin Kvarnung, Katrina Tatton-Brown, Diana Baralle, Zeynep Tümer, Allan Bayat*

*Corresponding author for this work

Abstract

Ionotropic 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.

Original languageEnglish
JournalClinical Genetics
Volume106
Issue number4
Pages (from-to)427-436
Number of pages10
ISSN0009-9163
DOIs
Publication statusPublished - Oct 2024

Keywords

  • Humans
  • Neurodevelopmental Disorders/genetics
  • Female
  • Male
  • Child
  • Receptors, AMPA/genetics
  • Adult
  • Child, Preschool
  • Adolescent
  • Phenotype
  • Mutation
  • Intellectual Disability/genetics
  • Genetic Predisposition to Disease
  • Young Adult

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