1. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome
- Author
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Kristin D. Kernohan, Sara Ellingwood, Jaime Barea, Christoffer Nellåker, Simon Sadedin, Katrin Õunap, Taila Hartley, Margarete Koch-Hogrebe, Marjan M. Nezarati, Augusta M. A. Lachmeijer, Dagmar Wieczorek, Elizabeth J. Bhoj, Paul J. Lockhart, Kym M. Boycott, Aren E Marshall, Tiong Yang Tan, Sander Pajusalu, Arran McBride, John Christodoulou, Michelle E. Ernst, Alison S May, Rami Abou Jamra, Susan M. White, Dong Li, K.L.I. van Gassen, and Wendy E. Smith
- Subjects
Male ,Adolescent ,DNA Repair ,DNA damage ,DNA repair ,medicine.disease_cause ,Chromatin remodeling ,03 medical and health sciences ,DDB1 ,Report ,Histone methylation ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Alleles ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,030305 genetics & heredity ,Syndrome ,Hypotonia ,Ubiquitin ligase ,DNA-Binding Proteins ,Phenotype ,Neurodevelopmental Disorders ,Child, Preschool ,biology.protein ,Female ,medicine.symptom - 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.
- Published
- 2021