Evaluation of non-coding variation in GLUT1 deficiency.
OBJECTIVE
Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants.


METHODS
We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant.


RESULTS
The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript.


CONCLUSIONS
Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes.
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.|Population Health and Immunity Division, The Walter and Eliza Hall Institute, Parkville, Vic., Australia.
Yu-Chi
YC
Liu
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.
Jia Wei Audrey
JW
Lee
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.
Susannah T
ST
Bellows
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.
John A
JA
Damiano
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.|Florey Institute, Heidelberg, Vic., Australia.
Saul A
SA
Mullen
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.
Samuel F
SF
Berkovic
Population Health and Immunity Division, The Walter and Eliza Hall Institute, Parkville, Vic., Australia.
Melanie
M
Bahlo
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.|Florey Institute, Heidelberg, Vic., Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Vic., Australia.
Ingrid E
IE
Scheffer
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Vic., Australia.
Michael S
MS
Hildebrand
D000328:Adult; D002239:Carbohydrate Metabolism, Inborn Errors / Q000134:cerebrospinal fluid* / Q000235:genetics*; D002675:Child, Preschool; D004827:Epilepsy / Q000134:cerebrospinal fluid* / Q000235:genetics*; D059472:Exome; D005260:Female; D005947:Glucose / Q000134:cerebrospinal fluid*; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000134:cerebrospinal fluid / Q000172:deficiency* / Q000235:genetics; D010375:Pedigree; D017421:Sequence Analysis
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; D005947:Glucose