SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
Author
Radio, Francesca Clementina
Pang, Kaifang
Ciolfi, Andrea
Levy, Michael A.
Hernández-García, Andrés
Pedace, Lucia
Pantaleoni, Francesca
Liu, Zhandong
de Boer, Elke
Jackson, Adam
Bruselles, Alessandro
McConkey, Haley
Stellacci, Emilia
Lo Cicero, Stefania
Motta, Marialetizia
Carrozzo, Rosalba
Dentici, Maria Lisa
McWalter, Kirsty
Desai, Megha
Monaghan, Kristin G.
Telegrafi, Aida
Philippe, Christophe
Vitobello, Antonio
Au, Margaret
Grand, Katheryn
Sanchez-Lara, Pedro A.
Baez, Joanne
Lindstrom, Kristin
Kulch, Peggy
Sebastian, Jessica
Madan-Khetarpal, Suneeta
Roadhouse, Chelsea
MacKenzie, Jennifer J.
Monteleone, Berrin
Saunders, Carol J.
Jean Cuevas, July K.
Cross, Laura
Zhou, Dihong
Hartley, Taila
Sawyer, Sarah L.
Monteiro, Fabíola Paoli
Secches, Tania Vertemati
Kok, Fernando
Schultz-Rogers, Laura E.
Macke, Erica L.
Morava, Eva
Klee, Eric W.
Kemppainen, Jennifer
Iascone, Maria
Selicorni, Angelo
Tenconi, Romano
Amor, David J.
Pais, Lynn
Gallacher, Lyndon
Turnpenny, Peter D.
Stals, Karen
Ellard, Sian
Cabet, Sara
Lesca, Gaetan
Pascal, Joset
Steindl, Katharina
Ravid, Sarit
Weiss, Karin
Castle, Alison M. R.
Carter, Melissa T.
Kalsner, Louisa
de Vries, Bert B. A.
van Bon, Bregje W.
Wevers, Marijke R.
Pfundt, Rolph
Stegmann, Alexander P. A.
Kerr, Bronwyn
Kingston, Helen M.
Chandler, Kate E.
Sheehan, Willow
Elias, Abdallah F.
Shinde, Deepali N.
Towne, Meghan C.
Robin, Nathaniel H.
Goodloe, Dana
Vanderver, Adeline
Sherbini, Omar
Bluske, Krista
Hagelstrom, R. Tanner
Zanus, Caterina
Faletra, Flavio
Musante, Luciana
Kurtz-Nelson, Evangeline C.
Earl, Rachel K.
Anderlid, Britt-Marie
Morin, Gilles
van Slegtenhorst, Marjon
Diderich, Karin E. M.
Brooks, Alice S.
Gribnau, Joost
Boers, Ruben G.
Finestra, Teresa Robert
Carter, Lauren B.
Rauch, Anita
Gasparini, Paolo
Boycott, Kym M.
Barakat, Tahsin Stefan
Graham, John M. Jr
Faivre, Laurence
Banka, Siddharth
Wang, Tianyun
Eichler, Evan E.
Priolo, Manuela
Dallapiccola, Bruno
Vissers, Lisenka E. L. M.
Sadikovic, Bekim
Scott, Daryl A.
Holder, Jimmy Lloyd Jr
Tartaglia, Marco
Date
2021-03-04Journal
American journal of human geneticsType
Journal ArticlePublisher
Cell PressDOI
10.1016/j.ajhg.2021.01.015Rights
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.Metadata
Show full item recordAbstract
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
Citation
Radio, F. C. et al. (2021) ‘SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.’, American journal of human genetics, 108(3), pp. 502–516. doi: 10.1016/j.ajhg.2021.01.015.Note
The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Collections
Except where otherwise noted, this item's license is described as Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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