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Am J Hum Genet. 2018 Mar 1;102(3):468-479. doi: 10.1016/j.ajhg.2018.01.014. Epub 2018 Feb 8.

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

Author information

1
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Experimental Renal and Cardiovascular Research, Institute of Pathology, Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
3
Génétique Clinique, Centre Hospitalier Universitaire de Caen, Caen 14000, France.
4
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
5
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
6
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
7
Clinical Genetics Service, University Hospitals of Bristol NHS Foundation Trust, Bristol BS2 8HW, UK.
8
Merseyside and Cheshire Clinical Genetics Service, Liverpool Women's NHS Foundation Hospital Trust, Liverpool L8 7SS, UK.
9
Genetikum Neu-Ulm, 89231 Neu-Ulm, Germany.
10
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
11
Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
12
Pediatric Genetics, University of Illinois Hospital, Chicago, IL 60612, USA.
13
GeneDx, Gaithersburg, MD 20877, USA.
14
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
15
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany; Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
16
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
17
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
18
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: andre.reis@uk-erlangen.de.

Abstract

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.

KEYWORDS:

BAF complex; Coffin-Siris syndrome; DPF2; PHD finger; autism spectrum disorder; dominant negative; histone modification; intellectual disability; nail hypoplasia; nuclear aggregates

PMID:
29429572
PMCID:
PMC5985265
DOI:
10.1016/j.ajhg.2018.01.014
[Indexed for MEDLINE]
Free PMC Article

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