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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620570
Title:
HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.
Authors:
Moortgat, S.; Berland, S.; Aukrust, I.; Maystadt, I.; Baker, L.; Benoit, V.; Caro-Llopis, A.; Cooper, N. S.; Debray, F-G; Faivre, L.; Gardeitchik, T.; Haukanes, B. I.; Houge, G.; Kivuva, Emma; Martinez, F.; Mehta, S. G.; Nassogne, M-C; Powell-Hamilton, N.; Pfundt, R.; Rosello, M.; Prescott, T.; Vasudevan, P.; van Loon, B.; Verellen-Dumoulin, C.; Verloes, A.; Lippe, C. von der; Wakeling, E.; Wilkie, A. O. M.; Wilson, L.; Yuen, A.; Study, D.; Low, K. J.; Newbury-Ecob, R. A.
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.
Citation:
HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. 2017 Eur. J. Hum. Genet.
Publisher:
Nature
Journal:
European journal of human genetics : EJHG
Issue Date:
27-Nov-2017
URI:
http://hdl.handle.net/11287/620570
DOI:
10.1038/s41431-017-0038-6
PubMed ID:
29180823
Additional Links:
http://dx.doi.org/10.1038/s41431-017-0038-6
Type:
Journal Article
Language:
en
ISSN:
1476-5438
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMoortgat, S.en
dc.contributor.authorBerland, S.en
dc.contributor.authorAukrust, I.en
dc.contributor.authorMaystadt, I.en
dc.contributor.authorBaker, L.en
dc.contributor.authorBenoit, V.en
dc.contributor.authorCaro-Llopis, A.en
dc.contributor.authorCooper, N. S.en
dc.contributor.authorDebray, F-Gen
dc.contributor.authorFaivre, L.en
dc.contributor.authorGardeitchik, T.en
dc.contributor.authorHaukanes, B. I.en
dc.contributor.authorHouge, G.en
dc.contributor.authorKivuva, Emmaen
dc.contributor.authorMartinez, F.en
dc.contributor.authorMehta, S. G.en
dc.contributor.authorNassogne, M-Cen
dc.contributor.authorPowell-Hamilton, N.en
dc.contributor.authorPfundt, R.en
dc.contributor.authorRosello, M.en
dc.contributor.authorPrescott, T.en
dc.contributor.authorVasudevan, P.en
dc.contributor.authorvan Loon, B.en
dc.contributor.authorVerellen-Dumoulin, C.en
dc.contributor.authorVerloes, A.en
dc.contributor.authorLippe, C. von deren
dc.contributor.authorWakeling, E.en
dc.contributor.authorWilkie, A. O. M.en
dc.contributor.authorWilson, L.en
dc.contributor.authorYuen, A.en
dc.contributor.authorStudy, D.en
dc.contributor.authorLow, K. J.en
dc.contributor.authorNewbury-Ecob, R. A.en
dc.date.accessioned2017-12-18T14:30:24Z-
dc.date.available2017-12-18T14:30:24Z-
dc.date.issued2017-11-27-
dc.identifier.citationHUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. 2017 Eur. J. Hum. Genet.en
dc.identifier.issn1476-5438-
dc.identifier.pmid29180823-
dc.identifier.doi10.1038/s41431-017-0038-6-
dc.identifier.urihttp://hdl.handle.net/11287/620570-
dc.description.abstractWhole-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.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/s41431-017-0038-6en
dc.rightsArchived with thanks to European journal of human genetics : EJHGen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleHUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.en
dc.typeJournal Articleen
dc.identifier.journalEuropean journal of human genetics : EJHGen
dc.type.versionIn press (epub ahead of print)en

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.