Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL

Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-02-20
DOI
https://doi.org/10.1016/j.xhgg.2025.100419
Citations
1
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.81

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article

Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL

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1 citations
Human Genetics and Genomics Advances
RNA regulation and disease
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article

Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL

Heidi L. Rehm, John Gaitanis, Lynn Pais, Melanie O’Leary, Grace E. VanNoy, Sarah L. Stenton, Anne O’Donnell‐Luria, Vijay S Ganesh, Jialan Ma, Elizabeth Carbonell
article en
1 citations

Abstract

Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

Human Genetics and Genomics AdvancesVol. 6(2)
Broad Institute (US), Boston Children's Hospital (US), Harvard University (US), Brown University (US), Massachusetts General Hospital (US), Hasbro Children's Hospital (US), Center for Systems Biology (US)
Harvard Catalyst, Broad Institute, Chan Zuckerberg Initiative, Manton Center for Orphan Disease Research, Boston Children's Hospital, National Human Genome Research Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Openalex Percentile: Top 31%
RNA regulation and disease
0.81
DOIOpen Access PDFOpenAlex
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