Subject: USP9X
Year: 2020
Type: Article
Title: Missense variant contribution to USP9X-female syndrome
Author: Jolly Lachlan
Author: Parnell Euan
Author: Gardner Alison E.
Author: Corbett Mark A.
Author: Pérez-Jurado Luis A.
Author: Shaw Marie
Author: Lesca Gaetan
Author: Keegan Catherine
Author: Schneider Michael C.
Author: Griffin Emily
Author: Maier Felicitas
Author: Kiss Courtney
Author: Guerin Andrea
Author: Crosby Kathleen
Author: Rosenbaum Kenneth
Author: Tanpaiboon Pranoot
Author: Whalen Sandra
Author: Keren Boris
Author: McCarrier Julie
Author: Basel Donald
Author: Sadedin Simon
Author: White Susan M.
Author: Delatycki Martin B.
Author: Kleefstra Tjitske
Author: Küry Sébastien
Author: Brusco Alfredo
Author: Shukarova Angelovska, Elena
Author: Trajkova Slavica
Author: Yoon Sehoun
Author: Wood Stephen A.
Author: Piper Michael
Author: Penzes Peter
Author: Gecz Jozef
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 USP9Xfemale syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9Xfemale 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 assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
Publisher: Springer Verlag
Relation: npj Genomic Medicine
Identifier: oai:repository.ukim.mk:20.500.12188/15319
Identifier: http://hdl.handle.net/20.500.12188/15319Identifier: https://doi.org/10.1038/s41525-020-00162-9
