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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.

Original publication

DOI

10.1016/j.ajhg.2021.03.007

Type

Journal article

Journal

American journal of human genetics

Publication Date

04/2021

Volume

108

Pages

749 - 756

Addresses

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.

Keywords

Care4Rare Canada Consortium, Humans, Syndrome, DNA-Binding Proteins, DNA Repair, Phenotype, Mutation, Alleles, Adolescent, Child, Child, Preschool, Female, Male, Neurodevelopmental Disorders