Missense variant contribution to USP9X-female syndrome

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...

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Autores principales:	Lachlan A. Jolly, Euan Parnell, Alison E. Gardner, Mark A. Corbett, Luis A. Pérez-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, Simon Sadedin, Susan M. White, Martin B. Delatycki, Tjitske Kleefstra, Sébastien Küry, Alfredo Brusco, Elena Sukarova-Angelovska, Slavica Trajkova, Sehoun Yoon, Stephen A. Wood, Michael Piper, Peter Penzes, Jozef Gecz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/698c9b16e7d1463b82071a45d7227565
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spelling	oai:doaj.org-article:698c9b16e7d1463b82071a45d72275652021-12-02T16:18:09ZMissense variant contribution to USP9X-female syndrome10.1038/s41525-020-00162-92056-7944https://doaj.org/article/698c9b16e7d1463b82071a45d72275652020-12-01T00:00:00Zhttps://doi.org/10.1038/s41525-020-00162-9https://doaj.org/toc/2056-7944Abstract 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 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.Lachlan A. JollyEuan ParnellAlison E. GardnerMark A. CorbettLuis A. Pérez-JuradoMarie ShawGaetan LescaCatherine KeeganMichael C. SchneiderEmily GriffinFelicitas MaierCourtney KissAndrea GuerinKathleen CrosbyKenneth RosenbaumPranoot TanpaiboonSandra WhalenBoris KerenJulie McCarrierDonald BaselSimon SadedinSusan M. WhiteMartin B. DelatyckiTjitske KleefstraSébastien KüryAlfredo BruscoElena Sukarova-AngelovskaSlavica TrajkovaSehoun YoonStephen A. WoodMichael PiperPeter PenzesJozef GeczNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 5, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Lachlan A. Jolly Euan Parnell Alison E. Gardner Mark A. Corbett Luis A. Pérez-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 Simon Sadedin Susan M. White Martin B. Delatycki Tjitske Kleefstra Sébastien Küry Alfredo Brusco Elena Sukarova-Angelovska Slavica Trajkova Sehoun Yoon Stephen A. Wood Michael Piper Peter Penzes Jozef Gecz Missense variant contribution to USP9X-female syndrome
description	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 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.
format	article
author	Lachlan A. Jolly Euan Parnell Alison E. Gardner Mark A. Corbett Luis A. Pérez-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 Simon Sadedin Susan M. White Martin B. Delatycki Tjitske Kleefstra Sébastien Küry Alfredo Brusco Elena Sukarova-Angelovska Slavica Trajkova Sehoun Yoon Stephen A. Wood Michael Piper Peter Penzes Jozef Gecz
author_facet	Lachlan A. Jolly Euan Parnell Alison E. Gardner Mark A. Corbett Luis A. Pérez-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 Simon Sadedin Susan M. White Martin B. Delatycki Tjitske Kleefstra Sébastien Küry Alfredo Brusco Elena Sukarova-Angelovska Slavica Trajkova Sehoun Yoon Stephen A. Wood Michael Piper Peter Penzes Jozef Gecz
author_sort	Lachlan A. Jolly
title	Missense variant contribution to USP9X-female syndrome
title_short	Missense variant contribution to USP9X-female syndrome
title_full	Missense variant contribution to USP9X-female syndrome
title_fullStr	Missense variant contribution to USP9X-female syndrome
title_full_unstemmed	Missense variant contribution to USP9X-female syndrome
title_sort	missense variant contribution to usp9x-female syndrome
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/698c9b16e7d1463b82071a45d7227565
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Missense variant contribution to USP9X-female syndrome

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