Related Experiment Video

Updated: Dec 15, 2025

Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
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Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons

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SLC6A1 G443D associated with developmental delay and epilepsy

Seth Devries1, Monica Mulder1, Jacob G Charron2

  • 1Pediatric Neurology, Helen DeVos Children's Hospital, Grand Rapids, Michigan 49503, USA.

Cold Spring Harbor Molecular Case Studies
|July 15, 2020
PubMed

Insights

The SLC6A1 gene variant G443D causes a severe neurological disorder. Computational analysis confirmed it as a loss-of-function variant, leading to drug-resistant epilepsy in a young girl.

Area of Science:

  • Genetics
  • Neuroscience
  • Computational Biology

Background:

  • The SLC6A1 gene is implicated in autosomal dominant epilepsy with intellectual disability.
  • Early-onset seizures and developmental delay are key features of SLC6A1-related disorders.

Observation:

  • A 2-year-old girl presented with developmental delay and epilepsy.
  • Genomic analysis identified a G443D variant in the SLC6A1 gene, initially of uncertain significance.

Findings:

  • Structural and evolutionary assessments, alongside computational tools (PolyPhen-2, PROVEAN, SIFT, Align-GVGD), classified the G443D variant as a loss-of-function.
  • This variant showed significant functional changes compared to known pathogenic variants in databases like gnomAD, TOPMed, and ClinVar.
  • The patient's epilepsy was resistant to multiple drugs but controlled by valproic acid.

Implications:

  • This study functionally characterizes a novel SLC6A1 variant, contributing to the understanding of epileptic encephalopathies.
  • The findings highlight the utility of integrated computational approaches for variant interpretation.
  • Valproic acid may be an effective treatment for patients with this specific SLC6A1 variant.

Keywords:
absence seizuresautismmoderate global developmental delay

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