Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Stankiewicz P, Khan TN, Szafranski P, Slattery L, Streff H, Vetrini F, Bernstein JA, Brown CW, Rosenfeld JA, Rednam S, Scollon S, Bergstrom KL, Parsons DW, Plon SE, Vieira MW, Quaio CRDC, Baratela WAR, Acosta Guio JC, Armstrong R, Mehta SG, Rump P, Pfundt R, Lewandowski R, Fernandes EM, Shinde DN, Tang S, Hoyer J, Zweier C, Reis A, Bacino CA, Xiao R, Breman AM, Smith JL, Katsanis N, Bostwick B, Popp B, Davis EE, Yang Y (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 101

Pages Range: 503-515

Journal Issue: 4

DOI: 10.1016/j.ajhg.2017.08.014

Abstract

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Authors with CRIS profile

Involved external institutions

Addenbrooke's Hospital United Kingdom (GB) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Radboud University Nijmegen Netherlands (NL) Virginia Commonwealth University (VCU) United States (USA) (US) Ambry Genetics United States (USA) (US) Houston Texas Medical Center United States (USA) (US) Duke University United States (USA) (US) Stanford University United States (USA) (US) Baylor Genetics United States (USA) (US) University of Tennessee (UTK) United States (USA) (US) Pontifícia Universidade Católica de São Paulo (PUCSP) Brazil (BR) Fleury Medicina e Saúde Brazil (BR) Instituto de Ortopedia Infantil Roosevelt Colombia (CO)

How to cite

APA:

Stankiewicz, P., Khan, T.N., Szafranski, P., Slattery, L., Streff, H., Vetrini, F.,... Yang, Y. (2017). Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features. American Journal of Human Genetics, 101(4), 503-515. https://dx.doi.org/10.1016/j.ajhg.2017.08.014

MLA:

Stankiewicz, Pawel, et al. "Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features." American Journal of Human Genetics 101.4 (2017): 503-515.

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