Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome

Journal article

Publication Details

Author(s): Vasileiou G, Vergarajauregui S, Endele S, Popp B, Büttner C, Ekici AB, Gerard M, Bramswig NC, Albrecht B, Clayton-Smith J, Morton J, Tomkins S, Low K, Weber A, Wenzel M, Altmueller J, Li Y, Wollnik B, Hoganson G, Plona MR, Cho MT, Thiel C, Luedecke HJ, Strom TM, Calpena E, Wilkie AOM, Wieczorek D, Engel F, Reis A
Journal: American Journal of Human Genetics
Publisher: CELL PRESS
Publication year: 2018
Volume: 102
Journal issue: 3
Pages range: 468-479
ISSN: 0002-9297


Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

FAU Authors / FAU Editors

Büttner, Christian
Lehrstuhl für Humangenetik
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Endele, Sabine Dr. rer. nat.
Humangenetisches Institut
Engel, Felix Prof. Dr. rer. nat.
Professur für Experimentelle Nieren- und Kreislaufforschung
Popp, Bernt Dr. med.
Humangenetisches Institut
Thiel, Christian PD Dr.
Medizinische Fakultät

External institutions with authors

Birmingham Women's NHS Foundation Trust
Centre Hospitalier Universitaire de Caen
genetikum® – Genetische Beratung & Diagnostik
Health Innovation Manchester
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU)
Liverpool Women's NHS Foundation Trust
Universität Duisburg-Essen (UDE)
Universität Köln
Universitätsklinikum Göttingen
University Hospitals Bristol NHS Foundation Trust
University of Illinois Hospital & Health Sciences System
University of Oxford

How to cite

Vasileiou, G., Vergarajauregui, S., Endele, S., Popp, B., Büttner, C., Ekici, A.B.,... Reis, A. (2018). Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome. American Journal of Human Genetics, 102(3), 468-479.

Vasileiou, Georgia, et al. "Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome." American Journal of Human Genetics 102.3 (2018): 468-479.


Last updated on 2019-21-07 at 08:04