Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.
AMPAR
GRIA1
autonomy
developmental trajectory
epilepsy
natural history
outcome
syndrome
treatment
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
18 Jun 2024
18 Jun 2024
Historique:
revised:
29
05
2024
received:
23
04
2024
accepted:
06
06
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
19
6
2024
Statut:
aheadofprint
Résumé
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.
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