Locus GDPAG GLS

Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. This condition is caused by mutations in the glutaminase (GLS) gene¹.

Prevalence

As of 2019, only 7 cases total of GLS deficiency, including non-repeat. Identified unrelated patients have been Canadian², Kurdish (Turkey)³, and US-American (Northern European/Native American descent)³.

Age of Onset

Early childhood (2-4)^2,3.

HPO Terms

–

Association

Mendelian

Locus

hg19 chr2:191745598-191745646

hg38 chr2:190880872-190880920

t2t chr2:191369982-191370024

Details

Pathogenic range from 3 unrelated probands; benign range inferred from mutation data⁴. Disease cases can be caused by homozygosity or compound heterozygotes⁵.

Mechanism

LoF

Change in histone modification decreases transcription⁵.

Detection

Exome sequencing does not reliably detect these expansions. Short-read sequencing has flagged expanded alleles while RP-PCR has confirmed them. Complex alleles may require optical genome mapping or long-read sequencing to resolve size and structure [@pmid:30970188; @pmid:35913761].

Year

2019²

Location in Gene

5' UTR

Gene Strand

Alleles

Ref. Motif

GCA

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GCA

Pathogenic (gene)

AGC

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0600001

Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in

André B P,van Kuilenburg, Maja,Tarailo-Graovac, Phillip A,Richmond, Britt I,Drögemöller, Mahmoud A,Pouladi, René,Leen, Koroboshka,Brand-Arzamendi, Doreen,Dobritzsch, Egor,Dolzhenko, Michael A,Eberle, Bruce,Hayward, Meaghan J,Jones, Farhad,Karbassi, Michael S,Kobor, Janet,Koster, Daman,Kumari, Meng,Li, Julia,MacIsaac, Cassandra,McDonald, Judith,Meijer, Charlotte,Nguyen, Indhu-Shree,Rajan-Babu, Stephen W,Scherer, Bernice,Sim, Brett,Trost, Laura A,Tseng, Marjolein,Turkenburg, Joke J F A,van Vugt, Jan H,Veldink, Jagdeep S,Walia, Youdong,Wang, Michel,van Weeghel, Galen E B,Wright, Xiaohong,Xu, Ryan K C,Yuen, Jinqiu,Zhang, Colin J,Ross, Wyeth W,Wasserman, Michael T,Geraghty, Saikat,Santra, Ronald J A,Wanders, Xiao-Yan,Wen, Hans R,Waterham, Karen,Usdin, Clara D M,van Karnebeek

The New England journal of medicine · 2019-04-11

pmid:30970188

Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation.

Sarah,Fazal, Matt C,Danzi, André B P,van Kuilenburg, Selina,Reich, Andreas,Traschütz, Benjamin,Bender, René,Leen, Camilo,Toro, Karen,Usdin, Bruce,Hayward, David R,Adams, Clara D M,van Karnebeek, Carlos R,Ferreira, Precilla,D'Sousa, Undiagnosed Diseases,Network, Mustafa,Tekin, Stephan,Züchner, Matthis,Synofzik

Human molecular genetics · 2023-01-01

pmid:35913761

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

5omim:618412

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Insights into DNA repeat expansions among 900,000 biobank participants.

Margaux L A,Hujoel, Robert E,Handsaker, David,Tang, Nolan,Kamitaki, Ronen E,Mukamel, Simone,Rubinacci, Pier Francesco,Palamara, Steven A,McCarroll, Po-Ru,Loh

Nature · 2026-01-07

pmid:41501457

Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.

Wai Yan,Yau, Roisin,Sullivan, Emer,O'Connor, David,Pellerin, Michael H,Parkinson, Paola,Giunti, Marie-Josée,Dicaire, Matt C,Danzi, Stephan,Züchner, Bernard,Brais, Nicholas W,Wood, Henry,Houlden, Jana,Vandrovcova

Brain communications · 2025-05-17

pmid:40488180

A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.

Sarah,Fazal, Harriet,Dashnow, Maike F,Dohrn, Jacquelyn,Raposo, Laurel,Hiatt, Matt C,Danzi, Isaac R L,Xu, Camilo,Toro, David R,Adams, Karen,Usdin, Bruce,Hayward, Shilpa Nadimpalli,Kobren, Shamil R,Sunyaev, Rebecca C,Spillmann, Vandana,Shashi, Adriana,Rebelo, Guney,Bademci, Mustafa,Tekin, Aaron R,Quinlan, Stephan,Zuchner

Genetics in medicine : official journal of the American College of Medical Genetics · 2025-05-22

pmid:40417743

Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.

Lijing,Lei, Linliu,Peng, Linlin,Wan, Zhao,Chen, Chunrong,Wang, Huirong,Peng, Rong,Qiu, Beisha,Tang, Hong,Jiang

Movement disorders : official journal of the Movement Disorder Society · 2024-12-19

pmid:39699045

Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants.

Margaux L A,Hujoel, Robert E,Handsaker, Nolan,Kamitaki, Ronen E,Mukamel, Simone,Rubinacci, Pier F,Palamara, Steven A,McCarroll, Po-Ru,Loh

bioRxiv : the preprint server for biology · 2024-11-26

pmid:39651202

All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

Bruce,Hayward, Daman,Kumari, Saikat,Santra, Clara D M,van Karnebeek, André B P,van Kuilenburg, Karen,Usdin

Scientific reports · 2024-06-14

pmid:38877099

Identifying unstable CNG repeat loci in the human genome: a heuristic approach and implications for neurological disorders.

Varun,Suroliya, Bharathram,Uppili, Manish,Kumar, Vineet,Jha, Achal K,Srivastava, Mohammed,Faruq

Human genome variation · 2024-06-13

pmid:38871700

All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

Bruce,Hayward, Daman,Kumari, Saikat,Santra, Clara D M,van Karnebeek, André B P,van Kuilenburg, Karen,Usdin

bioRxiv : the preprint server for biology · 2024-05-09

pmid:38260514

A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.

James J,Harding, Melinda,Telli, Pamela,Munster, Martin H,Voss, Jeffrey R,Infante, Angela,DeMichele, Mark,Dunphy, Mai H,Le, Chris,Molineaux, Keith,Orford, Frank,Parlati, Sam H,Whiting, Mark K,Bennett, Nizar M,Tannir, Funda,Meric-Bernstam

Clinical cancer research : an official journal of the American Association for Cancer Research · 2021-07-20

pmid:34285061