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.
Original language | English |
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Pages (from-to) | 64-74 |
Number of pages | 11 |
Journal | European Journal of Human Genetics |
Volume | 26 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2018 |
Bibliographical note
Funding Information:Acknowledgements We thank the patients, their families and the clinical staff worldwide for their participation. We thank the 'Fonds Marguerite-Marie Delacroix' for the research grant provided to S.M. This work was supported by the ‘Institut de Recherche Scientifique en Pathologie et Génétique’. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC), and the Norwegian Regional Committees for Medical and Health Research Ethics approval (2016/1909). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Spanish patient study was supported by grant PI14/00350 (Instituto de Salud Carlos III -Acción Estratégica en Salud 2013–2016; FEDER -Fondo Europeo de Desarrollo Regional). We also would like to thank G. Matre at Hau-keland University Hospital for performing all the RNA isolation and cDNA sequencing in this study. A.O.M.W. is supported by a Wellcome Senior Investigator Award (102731).
Publisher Copyright:
© 2017 European Society of Human Genetics.