A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.

Adolescent Alleles Child Child, Preschool DNA Repair / genetics DNA-Binding Proteins / genetics Female Humans Male Mutation Neurodevelopmental Disorders / genetics Phenotype Syndrome
CRL4 DDB1 intellectual disability mutation

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
01 04 2021
Historique:
received: 26 10 2020
accepted: 02 03 2021
pubmed: 21 3 2021
medline: 8 5 2021
entrez: 20 3 2021
Statut: ppublish

Résumé

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.

Identifiants

DOI: 10.1016/j.ajhg.2021.03.007 PMID: 33743206 PMC: PMC8059373
pubmed: 33743206
pii: S0002-9297(21)00091-4
doi: 10.1016/j.ajhg.2021.03.007
pmc: PMC8059373
pii:
doi:

Substances chimiques

DDB1 protein, human 0
DNA-Binding Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

749-756

Subventions

Organisme : Medical Research Council
ID : MR/M014568/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U01 HG009599
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : CIHR
Pays : Canada

Informations de copyright

Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Auteurs

Susan M White (SM)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: sue.white@vcgs.org.au.

Elizabeth Bhoj (E)

Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Christoffer Nellåker (C)

Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford OX3 7DQ, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK.

Augusta M A Lachmeijer (AMA)

Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.

Aren E Marshall (AE)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Kym M Boycott (KM)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Dong Li (D)

Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Wendy Smith (W)

Division of Genetics, Department of Paediatrics, Maine Medical Center, Portland, ME 04012, USA.

Taila Hartley (T)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Arran McBride (A)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Michelle E Ernst (ME)

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.

Alison S May (AS)

Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Dagmar Wieczorek (D)

Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf 40225, Germany.

Rami Abou Jamra (R)

Institute of Human Genetics, University Medical Center Leipzig, Leipzig 04103, Germany.

Margarete Koch-Hogrebe (M)

Vestische Kinder- und Jugendklinik Datteln, Universität Witten-Herdecke, Datteln 45711, Germany.

Katrin Õunap (K)

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, L. Puusepa 2, 51014 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, L. Puusepa 2, 51014 Tartu, Estonia.

Sander Pajusalu (S)

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, L. Puusepa 2, 51014 Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, L. Puusepa 2, 51014 Tartu, Estonia.

K L I van Gassen (KLI)

Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.

Simon Sadedin (S)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA 01242, USA.

Sara Ellingwood (S)

Division of Genetics, Department of Paediatrics, Maine Medical Center, Portland, ME 04012, USA.

Tiong Yang Tan (TY)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.

John Christodoulou (J)

Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.

Jaime Barea (J)

Rady Children's Specialists of San Diego, San Diego, CA 92123, USA.

Paul J Lockhart (PJ)

Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Marjan M Nezarati (MM)

North York General Hospital, Toronto, ON M2K 1E1, Canada.

Kristin D Kernohan (KD)

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Newborn Screening Ontario, Ottawa, ON K1H 8L1, Canada.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Phénomènes génétiques › Réparation de l'ADN › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › A DNA repair disorder caused by de novo...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › A DNA repair disorder caused by de novo...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Maladie › Syndrome › A DNA repair disorder caused by de novo...