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.
| Original language | English |
|---|---|
| Pages (from-to) | 468-479 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 102 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2018 |
Bibliographical note
Funding Information:We thank the individuals and their families for participating in this study. We also thank Juliane Hoyer and Michel Hadjihannas for useful advice. We are indebted to Daniela Schweitzer, Olga Zwenger, Angelika Diem, and Heike Friebel for excellent technical assistance. This work was supported by the German Federal Ministry of Research and Education (01GM1520A to A.R., 01GM1520B to N.B., 01GM1520D to T.S., and 01GM1520E to D.W.) as part of the Chromatin-Net Consortium, by Interdisciplinary Centre for Clinical Research Erlangen project E16 (A.R.), by the German Research Foundation (INST 410/91-1 FUGG to F.B.E), and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (AOMW) and Wellcome Trust (Senior Investigator Award 102731 to the AOMW). The Deciphering Developmental Disorders Study presents independent research commissioned by the Wellcome Trust Sanger Institute (grant WT098051) and the HealthInnovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health. The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network.
Publisher Copyright:
© 2018 American Society of Human Genetics
Keywords
- autism spectrum disorder
- BAF complex
- Coffin-Siris syndrome
- dominant negative
- DPF2
- histone modification
- intellectual disability
- nail hypoplasia
- nuclear aggregates
- PHD finger