Missense variant contribution to USP9X female syndrome

Anno:

2020

Lachlan A Jolly 1, Euan Parnell 2, Alison E Gardner 3, Mark A Corbett 3, Luis A Pérez-Jurado 3 4 5 6, Marie Shaw 3, Gaetan Lesca 7 8, Catherine Keegan 9, Michael C Schneider 10, Emily Griffin 11, Felicitas Maier 12, Courtney Kiss 13, Andrea Guerin 14, Kathleen Crosby 15, Kenneth Rosenbaum 15, Pranoot Tanpaiboon 15, Sandra Whalen 16, Boris Keren 17, Julie McCarrier 18, Donald Basel 18, Simon Sadedin 19 20 21, Susan M White 19 20 21, Martin B Delatycki 19 20 21, Tjitske Kleefstra 22, Sébastien Küry 23 24, Alfredo Brusco 25 26, Elena Sukarova-Angelovska 27, Slavica Trajkova 25, Sehoun Yoon 2, Stephen A Wood 28, Michael Piper 29 30, Peter Penzes 2, Jozef Gecz 31 32

Affiliations

1University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia. Lachlan.Jolly@adelaide.edu.au.

2Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA.

3University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia.

4Women's and Children's Hospital, Adelaide, SA, 5006, Australia.

5South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia.

6Hospital del Mar Research Institute (IMIM), Network Research Centre for Rare Diseases (CIBERER) and Universitat Pompeu Fabra, Barcelona, 08003, Spain.

7Institut Neuromyogène, métabolisme énergétique et développement durable, CNRS UMR 5310, INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

8Service de Génétique, Hospices Civils de Lyon, Lyon, France.

9Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

10Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA.

11Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.

12Dr. von Hauner Children's Hospital, LMU - Ludwig-Maximilians-Universität Munich, University of Munich Medical Center, Munich, Germany.

13Kingston Health Sciences Centre, Kingston, ON, K7L 2V7, Canada.

14Division of Medical Genetics, Department of Pediatrics, Kingston General Hospital, Kingston, ON, Canada.

15Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.

16Unité Fonctionnelle de génétique clinique, Hôpital Armand Trousseau, Assistance publique-Hôpitaux de Paris, Centre de Référence Maladies Rares des anomalies du développement et syndromes malformatifs, Paris, France.

17Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.

18Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

19Victorian Clinical Genetics Service, Melbourne, VIC, Australia.

20Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

21Murdoch Children's Research Institute, Melbourne, VIC, Australia.

22Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6500, HB, the Netherlands.

23Service de Génétique Médicale, CHU Nantes, 44093, Nantes, France.

24l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, 44007, Nantes, France.

25Department of Medical Sciences, University of Turin, Torino, Italy.

26Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy.

27Department of Endocronology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia.

28Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.

29School of Biomedical Sciences, University of Queensland, Brisbane, QLD, 4072, Australia.

30Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.

31University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia. Jozef.Gecz@adelaide.edu.au.

32South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia. Jozef.Gecz@adelaide.edu.au.

NPJ Genom Med . 2020 Dec 9;5(1):53. 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.