Evaluation of non-coding variation in GLUT1 deficiency.

Area of Science:

• Genetics
• Neurology
• Metabolic Disorders

Background:

• Glucose transporter-1 (GLUT-1) deficiency impairs glucose transport across the blood-brain barrier.
• Loss-of-function mutations in SLC2A1 are a known cause, but 10% of hypoglycorrhachia cases remain undiagnosed.

Purpose of the Study:

• To investigate the role of non-coding SLC2A1 variants in unexplained hypoglycorrhachia.
• To expand genetic screening beyond exonic regions for GLUT-1 deficiency diagnosis.

Main Methods:

• Whole exome sequencing of a proband with GLUT-1 phenotype.
• Sequencing of non-coding promoter and intronic regions in 55 additional patients.
• mRNA studies to assess the impact of identified variants.

Main Results:

• A de novo splice site mutation was found in the proband.
• Deep intronic SLC2A1 variants, including a recurrent one, were identified in 3 of 55 patients.
• The recurrent variant led to reduced SLC2A1 mRNA transcript levels.

Conclusions:

• Pathogenic SLC2A1 mutations, including deep intronic variants, are associated with low cerebrospinal fluid glucose levels.
• Screening non-coding regions aids in diagnosing more GLUT-1 deficiency cases.
• Early diagnosis facilitates ketogenic diet implementation for improved patient outcomes.