Am J Hum Genet. 2017 Oct 5;101(4):503-515. doi: 10.1016/j.ajhg.2017.08.014. Epub 2017 Sep 21.

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

Stankiewicz P¹, Khan TN², Szafranski P³, Slattery L⁴, Streff H³, Vetrini F⁵, Bernstein JA⁴, Brown CW⁶, Rosenfeld JA⁷, Rednam S⁸, Scollon S⁸, Bergstrom KL⁸, Parsons DW⁹, Plon SE⁹, Vieira MW¹⁰, Quaio CRDC¹¹, Baratela WAR¹¹, Acosta Guio JC¹², Armstrong R¹³, Mehta SG¹³, Rump P¹⁴, Pfundt R¹⁵, Lewandowski R¹⁶, Fernandes EM¹⁶, Shinde DN¹⁷, Tang S¹⁷, Hoyer J¹⁸, Zweier C¹⁸, Reis A¹⁸, Bacino CA⁷, Xiao R⁷, Breman AM⁷, Smith JL⁷; Deciphering Developmental Disorders Study, Katsanis N², Bostwick B³, Popp B¹⁸, Davis EE², Yang Y¹⁹.

Author information

1: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: pawels@bcm.edu.
2: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
3: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4: Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA 94305, USA.
5: Baylor Genetics, Houston, TX 77021, USA.
6: University of Tennessee Health Science Center, Memphis, TN 38163, USA; Le Bonheur Children's Hospital, Memphis, TN 38105, USA.
7: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
8: Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA.
9: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA.
10: PUCSP, Faculdade de Ciências Médicas e da Saúde, São Paulo 01221-020, Brazil.
11: Fleury Medicina e Saúde, São Paulo 04344-070, Brazil.
12: Especialista en Genética Médica, Instituto de Ortopedia Infantil Roosevelt, 17-50 Bogotá, Cundinamarca, Colombia.
13: East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
14: Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 AB Groningen, the Netherlands.
15: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
16: Virginia Commonwealth University, Richmond, VA 23298, USA.
17: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
18: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
19: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: yapingy@bcm.edu.

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.