Evidence map›Paper›PMID 39721588›Full record

ArticleAmerican journal of human genetics2025

Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability.

Pascale Sabeh, Samantha A Dumas, Claudia Maios, Hiba Daghar, Marek Korzeniowski, Justine Rousseau, Matthew Lines, Andrea Guerin, John J Millichap, Megan Landsverk and 59 more

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Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

69 authors.

Pascale SabehDepartment of Genetics, CHU Sainte-Justine, Montréal, QC, Canada.
Samantha A DumasDepartment of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA.
Claudia MaiosDepartment of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada.
Hiba DagharDepartment of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada.
Marek KorzeniowskiDepartment of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA.
Justine RousseauDepartment of Genetics, CHU Sainte-Justine, Montréal, QC, Canada.
Matthew LinesDepartment of Clinical and Metabolic Genetics, Alberta Children's Hospital, Calgary, AB, Canada.
Andrea GuerinDivision of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, ON, Canada.
John J MillichapDepartment of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Megan LandsverkSanford Research, Pediatrics and Rare Diseases Group, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA.
Theresa GrebeDepartment of Genetics and Metabolism, Phoenix Children Hospital, Phoenix, AZ, USA.
Kristin LindstromBioMarin Pharmaceutical, Inc., 105 Digital Dr., Novato, CA 94949, USA.
Jonathan StroberDepartment of Child Neurology, University of California, San Francisco, San Francisco, CA, USA.
Tarik Ait MouhoubDepartment of Genetic, University Hospital Center of Reims, Reims, France.
Christiane ZweierDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
Michelle SteinrathsDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Moritz HebebrandInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Bert CallewaertCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Monika Kautza-LuchtInstitute of Human Genetics, University Hospital of Schleswig-Holstein, Kiel, Germany.
Meret WeglerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Paul KruszkaGeneDx, Gaithersburg, MD, USA.
Candy KumpsCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Ehud BanneThe Genetic Institute, Wolfson Medical Center, Holon, Israel.
Marta Biderman WaberskiPediatric Specialists of Virginia, Fairfax, VA, USA.
Anne DieuxService de génétique clinique du CHU de Lille, Lille, France.
Sarah RaibleDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Ian KrantzDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Livija MedneDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kieran PechterDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Laurent VillardAix Marseille University, INSERM, Marseille Medical Genetics Center, MMG, Marseille, France; University of Florence, Florence, Italy.
Renzo GuerriniNeuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy.
Claudia BianchiniNeuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy.
Carmen BarbaNeuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy.
Davide MeiNeuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy.
Xavier BlancMedigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
Christine KallayRéseau Hospitalier Neuchâtelois, Neuchâtel, Switzerland.
Emmanuelle RanzaMedigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
Xiao-Ru YangDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Emily O'HeirCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kirsten A DonaldDepartment of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa.
Serini MurugasenDepartment of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa.
Zandre BruwerDepartment of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa.
Muge CalikogluUniversity of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA.
Jennifer M MathewsUniversity of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA.
Marion Lesieur-SebellinService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
Geneviève BaujatUniversity of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA.
Nicolas DeriveLaboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
Tyler Mark PiersonDepartments of Pediatrics and of Neurology, Guerin Children's Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Jill R MurrellDepartment of Pathology and Laboratory Medicine, Children's Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Amelle ShillingtonDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Clothilde OrmieresService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
Sophie RondeauService de médecine génomique des maladies rares, Necker Hospital, Paris, France.
André ReisInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Alberto Fernandez-JaenDepartment of Pediatric Neurology, Hospital Universitario Quirónsalud, Madrid, Spain.
Ping Yee Billie AuDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
David A SweetserCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Lauren C BriereCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nathalie CouqueDépartement de Génétique - UF de Génétique Moléculaire Hôpital Robert Debré, Paris, France.
Laurence PerrinDépartement de Génétique - UF de Génétique Moléculaire Hôpital Robert Debré, Paris, France.
Jennifer SchymickSanta Clara Valley Medical Center, San Jose, CA, USA.
Paul GueguenLaboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
Mathilde LefebvreUF de génétique clinique, Centre Hospitalier Régional d'Orléans, Orléans, France.
Michael Van AndelSanta Clara Valley Medical Center, San Jose, CA, USA.
Jane JuusolaGeneDx, Gaithersburg, MD, USA.
Stylianos E AntonarakisMedigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
J Alex ParkerDepartment of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada.
Barrington G BurnettDepartment of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA. Electronic address: barrington.burnett@usuhs.edu.
Philippe M CampeauDepartment of Genetics, CHU Sainte-Justine, Montréal, QC, Canada. Electronic address: p.campeau@umontreal.ca.

Funding

Rare genetic disorders in NeuroDev: Insight into the genetic and phenotypic heterogeneity of ID, ASD and ADHD in South African PopulationsU01MH119689 · NIMH · BROAD INSTITUTE, INC. · PI DONALD, KIRSTY, O'DONNELL-LURIA, ANNE · 2019 to 2023
$5.2M
NIMH NIH HHS U01 MH119689
6 · The paper itself

Abstract

E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.

Indexed as

Autistic DisorderCaenorhabditis elegansDevelopmental DisabilitiesHeterozygoteIntellectual DisabilityNeurodevelopmental DisordersUbiquitin-Protein LigasesAdolescentAdultAnimalsChildChild, PreschoolFemaleHumansInfantMaleUbiquitin-Protein LigasesUBR5 protein, humanautismautosomal dominantdevelopmental diseaseepilepsyintellectual disabilityMendelian phenotypemovement disordersubiquitinUBR5

Identifiers

PMID39721588
PMCPMC11739880

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.