Undiagnosed metabolic disordersGene: GLS
Comment on list classification: Upgraded from Red to Amber. There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) must first be validated within the Genomics England pipeline.
When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore keeping Amber until the STR is validated or additional cases arise.
Created: 19 Jan 2021, 11:12 a.m. | Last Modified: 19 Jan 2021, 11:12 a.m.
Panel Version: 1.440
Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Created: 19 Jan 2021, 10:51 a.m. | Last Modified: 19 Jan 2021, 10:51 a.m.
Panel Version: 1.437
GLS is associated with relevant phenotypes in OMIM, but currently is not in Gene2Phenoype.
- PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine (MIM# 618412). One patient also showed cerebellar atrophy.
All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
- PMID: 30575854 (2019) - Biallelic variants identified in two families with three individuals affected by neonatal lethal epileptic encephalopathy and respiratory insufficiency (MIM# 618328). The variants were predicted to result in loss of function, supported by elevated glutamine in all cases.
- PMID: 30239721 (2019) - One case reported with a de novo (i.e. monoallelic) gain-of-function variant, associated with profound developmental delay, infantile cataract, skin abnormalities, and glutamate excess (MIM# 618339). Functional analysis showed the variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS
Created: 19 Jan 2021, 10:50 a.m. | Last Modified: 19 Jan 2021, 10:50 a.m.
Panel Version: 1.436
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
This gene is recently confirmed to be a cause for intellectual disability, ataxia, optic atrophy and biochemical evidence of very high glutamine levels without hyperammonaemia. A series of 3 patients is in press (NEJM) and presented at SSIEM 2018. One of the mechanisms of inheritance in some patients is a large tandem repeat which may coexist with a point mutation on the other allele. One patient has been found to be homozygous for the tandem repeat. Patients may be investigated for elevated glutamine with this panel and analysis of GLS should certainly now be included.
Created: 21 Dec 2018, 3:56 p.m.
Intellectual disability; Ataxia; Optic Atrophy
Mode of pathogenicity
Cannot find association for variants in this gene and monogenic disease. Not found in Orphanet, Gene2Phenotype or OMIM associated with a disease.
Created: 23 Feb 2017, 5:14 p.m.
Mode of inheritance
Gene: gls has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: GLS were changed from Glucosidase 1 deficiency (Disorders of protein N-glycosylation) to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Publications for gene: GLS were set to 27604308
Mode of inheritance for gene: GLS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Tag STR tag was added to gene: GLS. Tag for-review tag was added to gene: GLS.
Construction of “Undiagnosed Metabolic Disorders” (UDM) panel • The 614 genes from the neurometabolic gene panel (PMID: 27604308) added • Green genes downloaded from V1 metabolic panels (Cerebral folate deficiency, Congenital disorders of glycosylation, Hyperammonaemia, Ketotic hypoglycaemia, Mitochondrial disorders, Mucopolysaccharideosis, Gaucher, Fabry, Peroxisomal disorders), sources replaced with "Expert review green", then loaded as a review onto UDM panel, resulting in 367 green genes and 333 red (therefore 86 new green genes included from the additional metabolic panels that weren't previously on the UDM panel) • Downloaded green genes from all panels. Removed genes from none V1 panels. Removed genes from the metabolic panels mentioned above. Compared the remaining genes with the red genes from UDM panel. Loaded as an "Expert review Amber" review to the overlapping genes, (the panel name where the genes came from was used as the phenotype) • Used variant information from PMID 27604308 to review the genes on this panel • Reviewed genes on UDM panel with genes from Emory "Inherited Metabolic Disorders: Sequencing Panel" and UKGTN “Inborn Errors of Metabolism 226 panel”, changing status where appropriate, added 14 UKGTN genes that had not be listed before • Review 10 red genes that had not previously been reviewed, 4/10 were reclassified as green • Review the remaining 145 red genes that had not previously been reviewed (shared between reviewers EM, RF, LD, AT, HB, ON & SL), resulting in 60 green, 11 amber, 70 red, 4 I don’t know reviews) • Reviewed genes from PMID: 24816252 as a publication to genes found in the Inborn error or metabolism Genes metabolomics GWAS paper (figure 5). 2 new genes added
GLS was added to Undiagnosed metabolic disorderspanel. Source: Expert Review Red Model of inheritance for gene GLS was set to Unknown
GLS was added to Undiagnosed metabolic disorderspanel. Sources: Literature
GLS was created by sleigh