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, Phan Q Duy Department of Neurosurgery, University of Virginia School of Medicine , Charlottesville, VA, 22908 , USA Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, 06510 , USA Department of Neuroscience, University of Virginia School of Medicine , Charlottesville, VA, 22908 , USA Search for other works by this author on: Oxford Academic Bettina Jux Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LiMES), University of Bonn , Bonn, 53012 , Germany Search for other works by this author on: Oxford Academic Shujuan Zhao Department of Genetics, School of Medicine, Washington University , St. Louis, MO, 63110 , USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic Kedous Y Mekbib Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, 06510 , USA Search for other works by this author on: Oxford Academic Evan Dennis Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic Weilai Dong Laboratory of Human Genetics and Genomics, The Rockefeller University , New York, NY, 10065 , USA Search for other works by this author on: Oxford Academic Carol Nelson-Williams Department of Genetics, Yale University School of Medicine , New Haven, CT, 06510 , USA Search for other works by this author on: Oxford Academic Neel H Mehta Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic John P Shohfi Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, 06510 , USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic Jane Juusola GeneDx, Gaithersburg , MD, 20877 , USA Search for other works by this author on: Oxford Academic
, Garrett Allington Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, 06510 , USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic Hannah Smith Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, 06510 , USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Search for other works by this author on: Oxford Academic Sandrine Marlin Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University , Paris, 75013 , France Search for other works by this author on: Oxford Academic Kahina Belhous Department of Radiology, Necker Children Hospital, Assistance Publique—Hôpitaux de Paris, University Paris 5 , Paris, 75004 , France Search for other works by this author on: Oxford Academic Berrin Monteleone Search for other works by this author on: Oxford Academic G Bradley Schaefer Section of Genetics and Metabolism, University of Arkansas for Medical Sciences , Little Rock, AR, 77205 , USA Search for other works by this author on: Oxford Academic Margareta D Pisarska Department of Obstretrics and Gynecology, Cedars-Sinai Medical Center , Los Angeles, CA, 90048 , USA Search for other works by this author on: Oxford Academic Jaime Vásquez Division of Clinical Genetics, NYU Langone Health, Long Island , Mineola, NY, 11501 , USA Search for other works by this author on: Oxford Academic Juviannee I Estrada-Veras Department of Surgery, Henry M Jackson Foundation for the Advancement of Military Medicine and Uniformed Services University of the Health Sciences , Bethesda, MD, 20817 , USA Pediatric Subspecialty Genetics Walter Reed National Military Medical Center , Bethesda, MD, 20889 , USA Search for other works by this author on: Oxford Academic Boris Keren Department of Genetics, APHP, Sorbonne Université, Pitié-Salpêtrière University Hospital , Paris, 75013 , France Search for other works by this author on: Oxford Academic Cyril Mignot Department of Genetics, APHP, Sorbonne Université, Pitié-Salpêtrière University Hospital , Paris, 75013 , France Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière University Hospital , Paris, 75013 , France Search for other works by this author on: Oxford Academic Leigh A Flore Division of Genetic, Genomic and Metabolic Disorders, Children's Hospital of Michigan, Detroit, MI, and Central Michigan University College of Medicine , Mount Pleasant, MI, 48858 , USA Search for other works by this author on: Oxford Academic Irene V Palafoll Centre de référence Anomalies du développement , CHU Grenoble-Alpes, Grenoble, 38700 , France Search for other works by this author on: Oxford Academic Seth L Alper Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School , Boston, MA, 02115 USA Broad Institute of Harvard and MIT , Cambridge, MA, 02142 , USA Search for other works by this author on: Oxford Academic Richard P Lifton Laboratory of Human Genetics and Genomics, The Rockefeller University , New York, NY, 10065 , USA Search for other works by this author on: Oxford Academic Shozeb Haider Search for other works by this author on: Oxford Academic Andres Moreno-De-Luca Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen’s University Faculty of Health Sciences, Kingston, ON, K7L 3N6 , Search for other works by this author on: Oxford Academic Sheng Chih Jin Department of Genetics, School of Medicine, Washington University , St. Louis, MO, 63110 , USA Department of Pediatrics, Washington University School of Medicine , St. Louis, MO, 063110 , USA Sheng Chih Jin, PhD, Assistant Professor of Genetics and Pediatrics, Washington University School of Medicine, 4515 McKinley Ave. St. Louis, MO, 63110, USA, E-mail: jin810@wustl.edu Search for other works by this author on: Oxford Academic Waldemar Kolanus Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LiMES), University of Bonn , Bonn, 53012 , Germany Correspondence may also be addressed to: Waldemar Kolanus, PhD, Life and Medical Sciences Institute (LIMES), University of Bonn, Carl-Troll-Str.31, 53115 Bonn, Germany, E-mail: wkolanus@uni-bonn.de Search for other works by this author on: Oxford Academic Kristopher T Kahle Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 , USA Broad Institute of Harvard and MIT , Cambridge, MA, 02142 , USA Division of Genetics and Genomics, Manton Center for Orphan Disease research, Department of pediatrics, and Howard Hughes Medical institute, Boston Children’s Hospital , Boston, MA, 02115 , USA Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital , Boston, MA, 02114 , USA Correspondence to: Kristopher T. Kahle, MD, PhD, Nicholas T. Zervas Endowed Chair in Neurosurgery, Harvard Medical School, Broad Institute of Harvard and MIT, 15 Parkman St. WACC 331, Boston, MA 02114, USA, E-mail: kahle.kristopher@mgh.harvard.edu Search for other works by this author on: Oxford Academic
https://orcid.org/0000-0002-5458-6129 Brain, awae175, https://doi.org/10.1093/brain/awae175
Published:
04 June 2024
Article history
Received:
26 October 2023
Revision received:
31 March 2024
Accepted:
06 May 2024
Published:
04 June 2024
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Phan Q Duy, Bettina Jux, Shujuan Zhao, Kedous Y Mekbib, Evan Dennis, Weilai Dong, Carol Nelson-Williams, Neel H Mehta, John P Shohfi, Jane Juusola, Garrett Allington, Hannah Smith, Sandrine Marlin, Kahina Belhous, Berrin Monteleone, G Bradley Schaefer, Margareta D Pisarska, Jaime Vásquez, Juviannee I Estrada-Veras, Boris Keren, Cyril Mignot, Leigh A Flore, Irene V Palafoll, Seth L Alper, Richard P Lifton, Shozeb Haider, Andres Moreno-De-Luca, Sheng Chih Jin, Waldemar Kolanus, Kristopher T Kahle, TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus, Brain, 2024;, awae175, https://doi.org/10.1093/brain/awae175
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Abstract
Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome.
Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia.
Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at hom*ologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain.
These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.
hydrocephalus, TRIM71, de novo variants, neural stem cells, brain development, structural brain disorders
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Topic:
- congenital abnormality
- mutation
- hydrocephalus
- arginine
- brain diseases
- child
- corpus callosum
- embryo
- genes
- morphogenesis
- pediatrics
- pregnancy trimester, first
- brain
- neurosurgical procedures
- proband
- mendelian inheritance in man, online
- developmental delay
- fetal ventriculomegaly
- congenital hydrocephalus
- brain development
- white matter
- neural stem cells
- exome
- processing bodies
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