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| Intellectual disability v11.45 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Intellectual disability v11.38 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from GLUT1 deficiency syndrome 1, 606777; GLUT1 deficiency syndrome 2, 612126; {Epilepsy, idiopathic generalized, suscpetibility to, 12}, 614847; Dystonia 9, 601042; GLUT1 DEFICIENCY SYNDROME TYPE 1 (GLUT1DS1) to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.37 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.933 | USP7 |
Rebecca Foulger commented on gene: USP7: PMID:30679821: Fountain et al., 2019 report on the clinical and genetic spectrum of 16 new and 7 previously reported (by PMID:26365382) individuals with USP7 heterozygous de novo variants. The variants include 2 deletions, 3 nonsense, 3 splice site variants and 8 missense variants. Speech delay was seen in 23/23 patients, and ID/DD was seen in 22/23 patients. Note that Patients 18 and 20 harbor additional variants in TMEM106B and SLC2A1, Patient 19 also has a de novo heterozygous 102.5-kb mosaic loss of uncertain significance at 10q21.1. |
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| Intellectual disability v2.695 | AGO1 | Louise Daugherty Added comment: Comment on publications: Added publications suggested from external expert review to support upgrading of the gene. Also added PMID: 29726122 (2018) that reports a novel 2.3 Mb, de novo, 1p34.3p34.2 deletion in a patient with who has a history of global developmental delay, mild intellectual disability, delayed bone age, bilateral vesicoureteral reflux, vocal cord paralysis, right aberrant subclavian artery, kyphoscoliosis, bilateral metatarsus adductus, and valgus knee deformity. This adds to the evolving genetic literature that haploinsufficiency of this region and genes other than AGO1, AGO3, GRIK3, SLC2A1, and RIMS3 may lead to the neurocognitive delays | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.558 | ODC1 |
Konstantinos Varvagiannis gene: ODC1 was added gene: ODC1 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ODC1 were set to 30239107; 30475435 Phenotypes for gene: ODC1 were set to Global developmental delay; Intellectual disability; Macrocephaly; Alopecia; Ectodermal dysplasia Penetrance for gene: ODC1 were set to unknown Review for gene: ODC1 was set to GREEN Added comment: PMIDs 30239107 and 30475435 report on 5 cases of de novo truncating ODC1 variants in unrelated families. One concerned a stillborn male. The 4 remaining individuals presented with a similar phenotype consisting of alopecia and other ectodermal anomalies, DD/ID, relative or absolute macrocephaly and common facial features. DD/ID was severe in some instances and many of these individuals had extensive prior testing for other disorders (Fragile-X, PTEN, SLC2A1, chromosomal disorders, etc). ODC1 (ornithine decarboxylase 1) converts enzymatically ornithine to putrescine. All variants reported to date are truncating but lead to gain-of-function. Specifically they affect a 37 amino acid c-terminal destabilization region critical for the degradation of ODC1 and - as a result - lead to increased levels of ODC1 as well as putrescine. A mouse model with identical phenotype has been described several years ago. The role of ODC inhibitors is extensively discussed in both publications. As a result, ODC1 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature, Expert Review |
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| Intellectual disability v2.468 | SLC2A1 | Louise Daugherty Source Victorian Clinical Genetics Services was added to SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | Ellen McDonagh classified SLC2A10 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | BRIDGE consortium edited their review of SLC2A10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A1 | BRIDGE consortium edited their review of SLC2A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | BRIDGE consortium edited their review of SLC2A10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A1 | BRIDGE consortium edited their review of SLC2A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | Louise Daugherty classified SLC2A10 as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | Louise Daugherty commented on SLC2A10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A10 | BRIDGE consortium reviewed SLC2A10 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A1 | BRIDGE consortium reviewed SLC2A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | SLC2A1 | Sarah Leigh commented on SLC2A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||