Submission Details

SLC2A1 was first reported in relation to autosomal dominant GLUT1 Deficiency Syndrome in 1998 (Seidner et al., PMID: 9462754). SLC2A1 encodes GLUT-1, a facilitated glucose transporter, significantly expressed in the blood-brain barrier, placenta and erythrocytes, among other tissues. GLUT-1 deficiency syndrome is characterized by reduced glucose levels in the brain and CSF (hypoglycorrhachia), intellectual deficits, seizures, movement disorders, paroxysmal exercise-induced dyskinesia, and in some cases, hemolytic anemia, cation-leaky erythrocytes, stomatin-deficient cryohydrocytosis. In OMIM, SLC2A1 is associated with the following disease entities: Dystonia 9 (MIM: 601042); severe infantile-onset GLUT1 deficiency syndrome 1 (MIM: 606777); childhood-onset GLUT1 deficiency syndrome 2 (MIM: 612126); Stomatin-deficient cryohydrocytosis with neurologic defects (MIM: 608885); susceptibility to idiopathic generalized epilepsy 12 (MIM: 614847). And, in Orphanet, it is associated with childhood absence epilepsy (ORPHA:64280); Encephalopathy due to GLUT1 deficiency (ORPHA:71277); Hereditary cryohydrocytosis with reduced stomatin (ORPHA:168577); Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity (ORPHA:53583); and Paroxysmal exertion-induced dyskinesia (ORPHA:98811). The condition shows a phenotypic spectrum and heterogeneity and is reported to be a continuum in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1430/#glut1.Nomenclature). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. GLUT-1 deficiency syndrome is known to show intrafamilial and interfamilial variability (PMID: 27725288, 18451999). A ketogenic diet is effective in reducing seizure occurrences and improving gait disturbances (PMIDs: 9462754, 18451999, 22282645, 21555602, 21832227, 22492876). Therefore, all of the disease entities have been lumped into one disease entity, GLUT1 deficiency syndrome (MONDO:0000188).

At least 90 missense, nonsense, frameshift, in-frame and out-of-frame deletion, exon and whole gene deletion variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, segregation and experimental data.

Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 10 probands in 3 publications (PMID: 26193382, 9462754, 18451999). Variants in this gene segregated with disease in 11 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.

Heterozygous variants in SLC2A1 are the predominant cause of GLUT-1 deficiency syndrome. Most variants are de novo, but familial cases are also reported. The mechanism for disease is haploinsufficiency, causing reduced transport activity of the GLUT-1 protein (PMID: 9462754). At least three reports of autosomal recessive inheritance have been reported, in whom the severity of the disease was determined by the degree of haploinsufficiency (PMID: 20687207) of the protein. They have not been included in this curation, however. Complete loss of function of SLC2A1 is incompatible with life (PMID: 16497725).

Experimental Evidence: 4.5 POINTS This gene-disease association is supported by in vitro functional assays (PMID: 2348864, 10562431, 2710134) mouse models recapitulating the disease (PMID: 16497725, 16880609) and gene-therapy mediated rescue in mice (PMID: 28119822).

In summary, SLC2A1 is definitively associated with autosomal dominant GLUT1 deficiency syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autism and Intellectual Disability Gene Curation Expert Panel on 04/17/2019 (SOP Version 6).