Missense variant contribution to USP9X-female syndrome

Lachlan A Jolly,Sébastien Küry,Stephen A Wood,Susan White ,Slavica Trajkova,Michael Piper,Emily Griffin,Felicitas Maier,Alison Gardner ,Boris Keren,Kenneth N Rosenbaum ,Simon Sadedin,Sehyoun Yoon ,Mark Corbett ,Andrea Guerin,Euan Parnell,Pranoot Tanpaiboon,Sandra Whalen,Marie Shaw,Donald Basel,Peter Penzes,Alfredo Brusco,Julie Mccarrier,Courtney Kiss,Kathleen Crosby,Michael Schneider ,Martin B Delatycki,Elena Sukarova-Angelovska,Catherine E Keegan ,Luis A Pérez‐Jurado ,Gaëtan Lesca ,Tjitske Kleefstra,Jozef Gécz

doi: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 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.

Highlights

The deubiquitylating enzyme encoded by USP9X is best known for its roles in brain development and cancer[1]
We identify 10 novel female USP9X missense and is predicted to alter the intramolecular charge–charge interaction single amino acid deletion variants associated with neurodevelopmental disorders (NDDs), which with p.Gln1796, and as such constrict the ubiquitin binding alter generally invariable amino acids and are located in protein channel and sterically clash with the backbone amine of the regions required for catalytic activity and/or intolerant to variation. p.Leu[73] residue of ubiquitin
The remaining case of Female 33, with a variant inherited from her unaffected mother, who is unlikely a somatic mosaic, suggests possible modifier(s) of female penetrance, perhaps similar to e.g. the X-chromosome linked PCDH19 clustering epilepsy[24]

Summary

Introduction

The deubiquitylating enzyme encoded by USP9X is best known for its roles in brain development and cancer[1]. It is ranked among the top 5% of evolutionary constrained genes and is highly intolerant to variation (pLI = 1.0; z-score = 6.35)[1,2,3,4]. It is essential for embryonic viability[5]. USP9X functions to reverse the effects of protein ubiquitylation, a frequent post-translational modification that often culminates in protein degradation via the proteasome[6]. USP9X protects many of its substrates from degradation, thereby increasing their abundance and function[1].

Methods

Results

Conclusion