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

Susan M White; Elizabeth Bhoj; Christoffer Nellåker; Augusta M A Lachmeijer; Aren E Marshall; Kym M Boycott; Dong Li; Wendy Smith; Taila Hartley; Arran McBride; Michelle E Ernst; Alison S May; Dagmar Wieczorek; Rami Abou Jamra; Margarete Koch-Hogrebe; Katrin Õunap; Sander Pajusalu; K L I van Gassen; Simon Sadedin; Sara Ellingwood; Tiong Yang Tan; John Christodoulou; Jaime Barea; Paul J Lockhart; Care4Rare Canada Consortium; Marjan M Nezarati; Kristin D Kernohan

doi:10.1016/j.ajhg.2021.03.007

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

Am J Hum Genet. 2021 Apr 1;108(4):749-756. doi: 10.1016/j.ajhg.2021.03.007. Epub 2021 Mar 19.

Authors

Susan M White¹, Elizabeth Bhoj², Christoffer Nellåker³, Augusta M A Lachmeijer⁴, Aren E Marshall⁵, Kym M Boycott⁵, Dong Li², Wendy Smith⁶, Taila Hartley⁵, Arran McBride⁵, Michelle E Ernst⁷, Alison S May⁸, Dagmar Wieczorek⁹, Rami Abou Jamra¹⁰, Margarete Koch-Hogrebe¹¹, Katrin Õunap¹², Sander Pajusalu¹², K L I van Gassen⁴, Simon Sadedin¹³, Sara Ellingwood⁶, Tiong Yang Tan¹⁴, John Christodoulou¹⁵, Jaime Barea¹⁶, Paul J Lockhart¹⁵; Care4Rare Canada Consortium⁵; Marjan M Nezarati¹⁷, Kristin D Kernohan¹⁸

Affiliations

¹ 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.
² Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ 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.
⁴ Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.
⁵ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
⁶ Division of Genetics, Department of Paediatrics, Maine Medical Center, Portland, ME 04012, USA.
⁷ 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.
⁸ Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁹ Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf 40225, Germany.
¹⁰ Institute of Human Genetics, University Medical Center Leipzig, Leipzig 04103, Germany.
¹¹ Vestische Kinder- und Jugendklinik Datteln, Universität Witten-Herdecke, Datteln 45711, Germany.
¹² 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.
¹³ 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.
¹⁴ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁵ Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁶ Rady Children's Specialists of San Diego, San Diego, CA 92123, USA.
¹⁷ North York General Hospital, Toronto, ON M2K 1E1, Canada.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Newborn Screening Ontario, Ottawa, ON K1H 8L1, Canada.

Abstract

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.

Keywords: CRL4; DDB1; intellectual disability; mutation.

Publication types

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

MeSH terms

Adolescent
Alleles*
Child
Child, Preschool
DNA Repair / genetics*
DNA-Binding Proteins / genetics*
Female
Humans
Male
Mutation*
Neurodevelopmental Disorders / genetics*
Phenotype
Syndrome

Substances

DDB1 protein, human
DNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding