Likely inborn error of metabolism

Gene: GLS

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed

Created: 3 Mar 2022, 12:59 p.m. | Last Modified: 3 Mar 2022, 12:59 p.m.

Panel Version: 2.223

Green List (high evidence)

Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.

Created: 11 Nov 2021, 10:03 a.m. | Last Modified: 11 Nov 2021, 10:03 a.m.

Panel Version: 2.195

Comment on list classification: There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) has not yet been 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 this gene is tagged 'for-review' to assess whether it should be downgraded to Amber until the STR is validated or additional cases arise.

Created: 19 Jan 2021, 11:23 a.m. | Last Modified: 19 Jan 2021, 11:23 a.m.

Panel Version: 2.48

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, 11:17 a.m. | Last Modified: 19 Jan 2021, 11:17 a.m.

Panel Version: 2.45

GLS is associated with relevant phenotypes in OMIM, but currently is not in Gene2Phenoype.
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- 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, 11:16 a.m. | Last Modified: 19 Jan 2021, 11:16 a.m.

Panel Version: 2.44

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
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

• 30970188
• 30575854
• 30239721

Green List (high evidence)

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.

Phenotypes
Intellectual disability; Ataxia; Optic Atrophy

Publications

• 29468182

Mode of pathogenicity
Other

I don't know

Comment on phenotypes: This gene now appears in OMIM with a disease due to new publications.

Created: 4 Dec 2019, 4:16 p.m. | Last Modified: 4 Dec 2019, 4:16 p.m.

Panel Version: 1.414

Comment on list classification: Due to expert review, evidence of 2 unrelated families for loss-of-function variants and further evidence for the role of this gene with an STR reported, this gene has been promoted from Red to Green.

Created: 4 Dec 2019, 4:15 p.m. | Last Modified: 4 Dec 2019, 4:15 p.m.

Panel Version: 1.413

Comment on publications: PMID: 30575854 - 2 families reported with 4 infants who had homozyous/compound heterozygous loss-of-function variants in this gene resulting in early neonatal epileptic encephalopathy with glutaminase deficiency and a lethal outcome.

Created: 4 Dec 2019, 4:10 p.m. | Last Modified: 4 Dec 2019, 4:10 p.m.

Panel Version: 1.411

Comment on publications: PMID: 30970188 - short tandem repeat (STR) reported in this gene to cause an inborn error of metabolism.

Created: 4 Dec 2019, 4:09 p.m. | Last Modified: 4 Dec 2019, 4:09 p.m.

Panel Version: 1.410

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
Unknown

Publications

• 27604308