Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.
Clin Genet
; 106(4): 427-436, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-38890806
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, AMPA
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Neurodevelopmental Disorders
Limits:
Adolescent
/
Adult
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Child
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Child, preschool
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Female
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Humans
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Male
Language:
En
Journal:
Clin Genet
Year:
2024
Document type:
Article