Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS | Zendy

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

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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS

Author(s) -

André B. P. Kuilenburg,

Maja TarailoGraovac,

Phillip A. Richmond,

Britt I. Drögemöller,

Mahmoud A. Pouladi,

René Leen,

Koroboshka BrandArzamendi,

Doreen Dobritzsch,

Egor Dolzhenko,

Michael A. Eberle,

Bruce E. Hayward,

Meaghan J. Jones,

Farhad Karbassi,

Michael S. Kobor,

Janet Koster,

Daman Kumari,

Meng Li,

Julia L. MacIsaac,

Cassandra McDonald,

Judith Meijer,

Charlotte Nguyen,

IndhuShree RajanBabu,

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.D. Ross,

Wyeth W. Wasserman,

Michael T. Geraghty,

Saikat Santra,

Ronald J. A. Wanders,

XiaoYan Wen,

Hans R. Waterham,

Karen Usdin,

Clara D. van Karnebeek

Publication year - 2019

Publication title -

new england journal of medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.889

H-Index - 1030

eISSN - 1533-4406

pISSN - 0028-4793

DOI - 10.1056/nejmoa1806627

Subject(s) - trinucleotide repeat expansion , ataxia , biology , genetics , exome sequencing , tandem repeat , untranslated region , genome , allele , rna , gene , mutation , neuroscience

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase ( GLS ) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

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