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Eur J Hum Genet. 2018 Jan;26(1):64-74. doi: 10.1038/s41431-017-0038-6. Epub 2017 Nov 27.

HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

Author information

1
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Charleroi (Gosselies), Belgium. stephanie.moortgat@ipg.be.
2
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
3
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Charleroi (Gosselies), Belgium.
4
Department of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
5
Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
6
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
7
Department of Medical Genetics, CHU Sart-Tilman, Liège, Belgium.
8
Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies Du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
9
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
10
Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, EX1 2ED, UK.
11
East Anglian Medical Genetics Service, Cambridge, UK.
12
Département de Neuropédiatrie, Cliniques Universitaires Saint-Luc, Brussels, 1200, Belgium.
13
Department of Medical Genetics, Telemark Hospital, Skien, Norway.
14
Department of Clinical Genetics, University Hospitals of Leicester, Leicester, UK.
15
Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway.
16
Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
17
Departement of Medical Genetics, Trondheim University Hospital, Trondheim, Norway.
18
North West Thames Regional Genetics Service, London North West Hospitals NHS Trust, Harrow, UK.
19
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
20
Clinical Genetics, Great Ormond Street Hospital for Children NHS foundation Trust, London, UK.
21
Genomics Institute, MultiCare Health System, Tacoma, WA, USA.
22
Wellcome Trust Sanger Institute, Cambridgeshire, UK.
23
University Hospitals Bristol NHS Trust/University of Bristol, Bristol, UK.

Abstract

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G  >  A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

PMID:
29180823
PMCID:
PMC5788272
DOI:
10.1038/s41431-017-0038-6
[Indexed for MEDLINE]
Free PMC Article

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