WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620408
Title:
WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.
Authors:
Skraban, C. M.; Wells, C. F.; Markose, P.; Cho, M. T.; Nesbitt, A. I.; Au, P Y B; Begtrup, A.; Bernat, J. A.; Bird, L. M; Cao, K.; de Brouwer, A P M; Denenberg, E H; Douglas, G; Gibson, K M; Grand, K; Goldenberg, A; Innes, A M; Juusola, J; Kempers, M; Kinning, E; Markie, D M; Owens, Martina; Payne, K; Person, R; Pfundt, R; Stocco, A; Turner, Claire L.; Verbeek, N E; Walsh, L E; Warner, T C; Wheeler, P G; Wieczorek, D; Wilkens, A B; Zonneveld-Huijssoon, E; Kleefstra, T; Robertson, S P; Santani, A; van Gassen, K L I; Deardorff, M A
Abstract:
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
Citation:
WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features. 2017, 101 (1):139-148 Am. J. Hum. Genet.
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
6-Jul-2017
URI:
http://hdl.handle.net/11287/620408
DOI:
10.1016/j.ajhg.2017.06.002
PubMed ID:
28686853
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30237-9
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Clinical Genetics (Peninsula Genetics); Molecular Genetics; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorSkraban, C. M.en
dc.contributor.authorWells, C. F.en
dc.contributor.authorMarkose, P.en
dc.contributor.authorCho, M. T.en
dc.contributor.authorNesbitt, A. I.en
dc.contributor.authorAu, P Y Ben
dc.contributor.authorBegtrup, A.en
dc.contributor.authorBernat, J. A.en
dc.contributor.authorBird, L. Men
dc.contributor.authorCao, K.en
dc.contributor.authorde Brouwer, A P Men
dc.contributor.authorDenenberg, E Hen
dc.contributor.authorDouglas, Gen
dc.contributor.authorGibson, K Men
dc.contributor.authorGrand, Ken
dc.contributor.authorGoldenberg, Aen
dc.contributor.authorInnes, A Men
dc.contributor.authorJuusola, Jen
dc.contributor.authorKempers, Men
dc.contributor.authorKinning, Een
dc.contributor.authorMarkie, D Men
dc.contributor.authorOwens, Martinaen
dc.contributor.authorPayne, Ken
dc.contributor.authorPerson, Ren
dc.contributor.authorPfundt, Ren
dc.contributor.authorStocco, Aen
dc.contributor.authorTurner, Claire L.en
dc.contributor.authorVerbeek, N Een
dc.contributor.authorWalsh, L Een
dc.contributor.authorWarner, T Cen
dc.contributor.authorWheeler, P Gen
dc.contributor.authorWieczorek, Den
dc.contributor.authorWilkens, A Ben
dc.contributor.authorZonneveld-Huijssoon, Een
dc.contributor.authorKleefstra, Ten
dc.contributor.authorRobertson, S Pen
dc.contributor.authorSantani, Aen
dc.contributor.authorvan Gassen, K L Ien
dc.contributor.authorDeardorff, M Aen
dc.date.accessioned2017-09-19T10:18:58Z-
dc.date.available2017-09-19T10:18:58Z-
dc.date.issued2017-07-06-
dc.identifier.citationWDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features. 2017, 101 (1):139-148 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid28686853-
dc.identifier.doi10.1016/j.ajhg.2017.06.002-
dc.identifier.urihttp://hdl.handle.net/11287/620408-
dc.description.abstractWe report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30237-9en
dc.rightsArchived with thanks to American journal of human geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleWDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.type.versionPublisheden

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