Missense variant contribution to USP9X-female syndrome
Journal
npj Genomic Medicine
Date Issued
2020
Author(s)
Jolly Lachlan
Parnell Euan
Gardner Alison E.
Corbett Mark A.
Pérez-Jurado Luis A.
Shaw Marie
Lesca Gaetan
Keegan Catherine
Schneider Michael C.
Griffin Emily
Maier Felicitas
Kiss Courtney
Guerin Andrea
Crosby Kathleen
Rosenbaum Kenneth
Tanpaiboon Pranoot
Whalen Sandra
Keren Boris
McCarrier Julie
Basel Donald
Sadedin Simon
White Susan M.
Delatycki Martin B.
Kleefstra Tjitske
Küry Sébastien
Brusco Alfredo
Trajkova Slavica
Yoon Sehoun
Wood Stephen A.
Piper Michael
Penzes Peter
Gecz Jozef
DOI
https://doi.org/10.1038/s41525-020-00162-9
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.
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.
Subjects
File(s)![Thumbnail Image]()
Loading...
Name
s41525-020-00162-9.pdf
Size
3.06 MB
Format
Adobe PDF
Checksum
(MD5):018228cc2d1aa075048f13b20860e69d