TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus

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

doi:10.1093/brain/awae175

TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus

Brain. 2024 Jun 4:awae175. doi: 10.1093/brain/awae175. Online ahead of print.

Authors

Phan Q Duy^{1

2

3}, Bettina Jux⁴, Shujuan Zhao^{5

6}, Kedous Y Mekbib^{6

2}, Evan Dennis⁶, Weilai Dong⁷, Carol Nelson-Williams⁸, Neel H Mehta⁶, John P Shohfi^{2

6}, Jane Juusola⁹, Garrett Allington^{2

6}, Hannah Smith^{2

6}, Sandrine Marlin¹⁰, Kahina Belhous¹¹, Berrin Monteleone¹², G Bradley Schaefer¹³, Margareta D Pisarska¹⁴, Jaime Vásquez¹², Juviannee I Estrada-Veras^{15

16}, Boris Keren¹⁷, Cyril Mignot^{17

18}, Leigh A Flore¹⁹, Irene V Palafoll²⁰, Seth L Alper^{21

22}, Richard P Lifton⁷, Shozeb Haider²³, Andres Moreno-De-Luca²⁴, Sheng Chih Jin^{5

25}, Waldemar Kolanus⁴, Kristopher T Kahle^{6

22

26

27}

Affiliations

¹ Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
² Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, 06510, USA.
³ Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
⁴ Molecular Immunology and Cell Biology, Life & Medical Sciences Institute (LiMES), University of Bonn, Bonn, 53012, Germany.
⁵ Department of Genetics, School of Medicine, Washington University, St. Louis, MO, 63110, USA.
⁶ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
⁷ Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, 10065, USA.
⁸ Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁹ GeneDx, Gaithersburg, MD, 20877, USA.
¹⁰ Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, 75013, France.
¹¹ Department of Radiology, Necker Children Hospital, Assistance Publique-Hôpitaux de Paris, University Paris 5, Paris, 75004, France.
¹² Division of Clinical Genetics, NYU Langone Health, Long Island, Mineola, NY, 11501, USA.
¹³ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 77205, USA.
¹⁴ Department of Obstretrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹⁵ 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.
¹⁶ Pediatric Subspecialty Genetics Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA.
¹⁷ Department of Genetics, APHP, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, 75013, France.
¹⁸ Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière University Hospital, Paris, 75013, France.
¹⁹ 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.
²⁰ Centre de référence Anomalies du développement, CHU Grenoble-Alpes, Grenoble, 38700, France.
²¹ 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.
²² Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
²³ School of Pharmacy, University College London, London, WC1E 6BT, UK.
²⁴ Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, ON, K7L 3N6, Canada.
²⁵ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 063110, USA.
²⁶ 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.
²⁷ Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA, 02114, USA.

PMID: 38833623
DOI: 10.1093/brain/awae175

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 homologous 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.

Keywords: TRIM71; brain development; de novo variants; hydrocephalus; neural stem cells; structural brain disorders.

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