Exploring gene-phenotype relationships in GRIN-related neurodevelopmental disorders
Jong Ho Cha1, Jee Min Kim1, Hee-Jeong Yun1
1Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, South Korea.
NPJ Genomic Medicine
|May 15, 2025
Summary
GRIN gene variants cause severe neurodevelopmental disorders, including profound global developmental delay (GDD). Specific missense variants in transmembrane helices M3/M4 are strongly linked to GDD, guiding personalized treatments.
Area of Science:
- Neuroscience
- Genetics
- Pediatric Neurology
Background:
- The GRIN gene family is associated with neurological conditions like global developmental delay (GDD) and epilepsy.
- GRIN-related disorders often lead to severe neurodevelopmental impairments.
Purpose of the Study:
- To analyze the clinical phenotypes and genetic variants in patients with GRIN-related neurodevelopmental disorders.
- To investigate the correlation between specific GRIN variant types and the severity of GDD and movement disorders.
- To identify specific GRIN variant locations associated with profound GDD.
Main Methods:
- Retrospective review of 31 patients with GRIN-related neurodevelopmental disorders at Seoul National University Hospital.
- Pooled analysis of patient data with information from the GRIN portal.
- Statistical analysis comparing outcomes based on variant type (missense/in-frame vs. protein-truncating) and location.
Main Results:
- All reviewed patients exhibited profound GDD; a majority had impaired motor and speech development.
- Missense or in-frame variants were significantly associated with higher rates of profound GDD and movement disorders compared to protein-truncating variants.
- Variants in the M3 and M4 helices of the transmembrane domain showed a significant association with profound GDD.
Conclusions:
- Detailed characterization of GRIN variants is crucial for understanding disease mechanisms.
- Variant type and location influence the severity of neurodevelopmental outcomes in GRIN-related disorders.
- Findings can inform the development of personalized treatment strategies for affected individuals.
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