Journal article

Missense variant contribution to USP9X-female syndrome

Lachlan A Jolly, Euan Parnell, Alison E Gardner, Mark A Corbett, Luis A Perez-Jurado, Marie Shaw, Gaetan Lesca, Catherine Keegan, Michael C Schneider, Emily Griffin, Felicitas Maier, Courtney Kiss, Andrea Guerin, Kathleen Crosby, Kenneth Rosenbaum, Pranoot Tanpaiboon, Sandra Whalen, Boris Keren, Julie McCarrier, Donald Basel Show all

npj Genomic Medicine | NATURE RESEARCH | Published : 2020

Abstract

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and ..

View full abstract

Grants

Awarded by SFARI Explorer Grant


Awarded by Australian Research Council


Awarded by National Health and Medical Research Council of Australia


Awarded by National Institute of Health


Awarded by Italian Ministry for Education, University and Research (Ministero dell'Istruzione, dell'Universita e della Ricerca - MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022"


Awarded by NIMH


Awarded by National Heart, Lung and Blood Institute


Awarded by National Human Genome Research Institute


Funding Acknowledgements

We are grateful for the support and contributions of all families involved in this study. We are thankful for the funding received from Creola Pora with the help of her friends and colleagues. This work was supported by SFARI Explorer Grant 527556 to M.P., S.A.W. and L.A.J. L.A.J. is supported by Australian Research Council ARC DE160100620. J.G. is supported by grants from the National Health and Medical Research Council of Australia: Program Grant (628952) and Research Fellowship (1041920). P.P. is supported by National Institute of Health grant R01MH107182. This research received funding specifically appointed to Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell'Istruzione, dell'Universita e della Ricerca - MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" Project code D15D18000410001. The whole-exome sequencing of Female 34 was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). Sequencing and analysis of Female 29 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141.