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

Elizabeth Carbonell; Sarah L Stenton; Vijay S Ganesh; Jialan Ma; Grace E VanNoy; Lynn Pais; John N Gaitanis; Melanie C O'Leary; Heidi L Rehm; Anne O'Donnell-Luria

doi:10.1016/j.xhgg.2025.100419

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

HGG Adv. 2025 Apr 10;6(2):100419. doi: 10.1016/j.xhgg.2025.100419. Epub 2025 Feb 21.

Authors

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Hasbro Children's Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.
⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA. Electronic address: odonnell@broadinstitute.org.

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.

Keywords: 5'UTR; GLUL; de novo; glutamine synthetase; seizures; start codon; start-loss.

Publication types

Case Reports

MeSH terms

Codon, Initiator* / genetics
Glutamate-Ammonia Ligase* / chemistry
Glutamate-Ammonia Ligase* / genetics
Humans
Male
Mutation*
Pedigree
Phenotype
Seizures* / diagnosis
Seizures* / genetics

Substances

Glutamate-Ammonia Ligase
Codon, Initiator