npj Genomic Medicine (Dec 2020)
Missense variant contribution to USP9X-female syndrome
- 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
Affiliations
- Lachlan A. Jolly
- University of Adelaide and Robinson Research Institute
- Euan Parnell
- Department of Physiology, Northwestern University Feinberg School of Medicine
- Alison E. Gardner
- University of Adelaide and Robinson Research Institute
- Mark A. Corbett
- University of Adelaide and Robinson Research Institute
- Luis A. Pérez-Jurado
- University of Adelaide and Robinson Research Institute
- Marie Shaw
- University of Adelaide and Robinson Research Institute
- Gaetan Lesca
- Institut Neuromyogène, métabolisme énergétique et développement durable, CNRS UMR 5310, INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1
- Catherine Keegan
- Division of Genetics, Department of Pediatrics, University of Michigan
- Michael C. Schneider
- Section of Neurology, Department of Pediatrics, St. Christopher’s Hospital for Children, Drexel University College of Medicine
- Emily Griffin
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center
- Felicitas Maier
- Dr. von Hauner Children’s Hospital, LMU - Ludwig-Maximilians-Universität Munich, University of Munich Medical Center
- Courtney Kiss
- Kingston Health Sciences Centre
- Andrea Guerin
- Division of Medical Genetics, Department of Pediatrics, Kingston General Hospital
- Kathleen Crosby
- Division of Genetics and Metabolism, Children’s National Hospital
- Kenneth Rosenbaum
- Division of Genetics and Metabolism, Children’s National Hospital
- Pranoot Tanpaiboon
- Division of Genetics and Metabolism, Children’s National Hospital
- Sandra Whalen
- Unité Fonctionnelle de génétique clinique, Hôpital Armand Trousseau, Assistance publique-Hôpitaux de Paris, Centre de Référence Maladies Rares des anomalies du développement et syndromes malformatifs
- Boris Keren
- Hôpital de la Pitié-Salpêtrière, Département de Génétique
- Julie McCarrier
- Division of Genetics, Department of Pediatrics, Medical College of Wisconsin
- Donald Basel
- Division of Genetics, Department of Pediatrics, Medical College of Wisconsin
- Simon Sadedin
- Victorian Clinical Genetics Service
- Susan M. White
- Victorian Clinical Genetics Service
- Martin B. Delatycki
- Victorian Clinical Genetics Service
- Tjitske Kleefstra
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
- Sébastien Küry
- Service de Génétique Médicale, CHU Nantes
- Alfredo Brusco
- Department of Medical Sciences, University of Turin
- Elena Sukarova-Angelovska
- Department of Endocronology and Genetics, University Clinic for Children’s Diseases, Medical Faculty, University Sv. Kiril i Metodij
- Slavica Trajkova
- Department of Medical Sciences, University of Turin
- Sehoun Yoon
- Department of Physiology, Northwestern University Feinberg School of Medicine
- Stephen A. Wood
- Griffith Institute for Drug Discovery, Griffith University
- Michael Piper
- School of Biomedical Sciences, University of Queensland
- Peter Penzes
- Department of Physiology, Northwestern University Feinberg School of Medicine
- Jozef Gecz
- University of Adelaide and Robinson Research Institute
- DOI
- https://doi.org/10.1038/s41525-020-00162-9
- Journal volume & issue
-
Vol. 5,
no. 1
pp. 1 – 11
Abstract
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.
