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
Affiliations
Elizabeth Carbonell
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Sarah L. Stenton
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
Vijay S. Ganesh
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
Jialan Ma
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Grace E. VanNoy
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lynn Pais
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
John N. Gaitanis
Hasbro Children’s Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Melanie C. O’Leary
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Heidi L. Rehm
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
Anne O’Donnell-Luria
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; Corresponding author
Summary: 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.
