Format

Send to

Choose Destination
Am J Hum Genet. 2016 Feb 4;98(2):373-81. doi: 10.1016/j.ajhg.2015.12.015. Epub 2016 Jan 28.

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations.

Author information

1
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
2
Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
3
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
4
Neurogenetics, School of Medicine and the Robinson Research Institute, the University of Adelaide, Adelaide, SA 5005, Australia.
5
Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands.
6
Department of Genetics, University of Groningen, University Medical Center of Groningen, 9700 RB Groningen, the Netherlands.
7
Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden.
8
The Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
10
Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
11
Department of Women's and Children's Health, Karolinska University Hospital, 171 76 Stockholm, Sweden.
12
Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
13
Department of Clinical Genetics, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
14
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
15
West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
16
Clinical Genetics Unit, Birmingham Women's NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2G, UK.
17
KK Women's and Children's Hospital, 229899 Singapore, Singapore.
18
Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
19
School of Biological Sciences, The University of Adelaide, Adelaide 5000, Australia.
20
Institute of Medical Biology, A(∗)STAR, 138648 Singapore, Singapore; Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, Reproductive Biology Laboratory (Q3-119), Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
21
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
22
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: ronald.roepman@radboudumc.nl.
23
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: tjitske.kleefstra@radboudumc.nl.

Abstract

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

PMID:
26833328
PMCID:
PMC4746365
DOI:
10.1016/j.ajhg.2015.12.015
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center