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Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation.

Published version
Peer-reviewed

Repository DOI


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Authors

Radford, Elizabeth J  ORCID logo  https://orcid.org/0000-0002-7829-5422
Tan, Hong-Kee 
Andersson, Malin HL  ORCID logo  https://orcid.org/0000-0003-1935-1989
Stephenson, James D 

Abstract

Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants. We identify 3432 functionally abnormal variants, in three distinct classes. We train a machine learning classifier to identify functionally abnormal variants of NDD-relevance. This classifier has at least 97% sensitivity and 99% specificity to detect variants pathogenic for NDD, substantially out-performing in silico predictors, and resolving up to 93% of variants of uncertain significance. Moreover, functionally-abnormal variants can account for almost all of the excess nonsynonymous DDX3X somatic mutations seen in DDX3X-driven cancers. Systematic maps of variant effects generated in experimentally tractable cell types have the potential to transform clinical interpretation of both germline and somatic disease-associated variation.

Description

Keywords

Female, Humans, Gene Editing, Virulence, Neurodevelopmental Disorders, Neoplasms, Germ Cells, Germ-Line Mutation, DEAD-box RNA Helicases

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/2)
MRC (MC_UU_00006/1)
MRC (MC_UU_00006/2)
MRC (MC_UU_00030/3)