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

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Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features Paweł Stankiewicz, Tahir N. Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A. Bernstein, Chester W. Brown, Jill A. Rosenfeld, Surya Rednam, Sarah Scollon, Katie L. Bergstrom, Donald W. Parsons, Sharon E. Plon, Marta W. Vieira, Caio R.D.C. Quaio, Wagner A.R. Baratela, Johanna C. Acosta Guio, Ruth Armstrong, Sarju G. Mehta, Patrick Rump, Rolph Pfundt, Raymond Lewandowski, Erica M. Fernandes, Deepali N. Shinde, Sha Tang, Juliane Hoyer, Christiane Zweier, André Reis, Carlos A. Bacino, Rui Xiao, Amy M. Breman, Janice L. Smith, Nicholas Katsanis, Bret Bostwick, Bernt Popp, Erica E. Davis, Yaping Yang The American Journal of Human Genetics Volume 101, Issue 4, Pages 503-515 (October 2017) DOI: 10.1016/j.ajhg.2017.08.014 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Clinical and Genetic Findings of Individuals with BPTF Variants (A) Clinical features of subjects 2 and 6–10. Note the lateral flaring of eyebrows, long nasal bridge, windswept 2nd toe with lateral deviation, and broad short great toe in subject 2; prominent nose and columella and thin upper lip and in subject 6; prominent supraorbital ridges, lateral flaring of eyebrows, short palpebral fissures, convergent squint, broad nasal tip, disorganized teeth, bulbous halluces, and overlapping toes in subject 7; short palpebral fissures, long nose, prominent ears, mildly hypolastic alae nasi full lower lip, micrognathia, and broad halluces in subject 8; long nasal bridge, small mouth, micrognathia, and sandal gap in subject 9; and telecanthus, prominent nasal root with mildly bulbous nasal tip, and micrognathia in subject 10. (B) A schematic of BPTF, the protein, and the effects of variants identified in this study. Domains represented in colors are: different transcription factors domain (DDT), PHD finger domain (PHD), and bromodomain (Bromo). The domain structure and amino acid numbering is based on the NCBI reference sequences GenBank: NP_003482.3 and NP_00450.3. (C) A schematic of chromosomal region 17q24.2 showing the deletions affecting BPTF in the UCSC browser. The American Journal of Human Genetics 2017 101, 503-515DOI: (10.1016/j.ajhg.2017.08.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 bptf CRISPR F0 Mutants Exhibit Microcephaly, Apoptosis in Anterior Structures, and Aberrant Patterning of the Branchial Arches (A) Representative dorsal images of 3 dpf zebrafish larvae show a reduction in head size (yellow dotted area) in F0 mutants. Scale bar (blue), 150 μm. (A′) Quantification of head size area in bptf F0 mutants (p ≤ 0.0001 versus control, n = 26–52 larvae/batch, repeated). Solid yellow line indicates scale bar. (B) Representative dorsal images of 2 dpf zebrafish larvae display increased apoptosis in the forebrain-midbrain region (blue dotted rectangle). (B′) Apoptotic cell count in bptf CRISPR F0 mutants (p = 0.0004 versus control, n = 20 larvae/condition per batch, repeated). (C) Representative dorsal images of 2 dpf zebrafish larvae do not show cell proliferation defects in anterior structures (blue dotted rectangle). (C′) Cell proliferation count in bptf CRISPR F0 mutants (n.s., no statistical significance, n = 20 larvae/condition per batch). (D) Representative ventral views of -1.4col1a1:egfp larvae imaged live at 3 dpf show an increase in the ceratohyal cartilage (CH; arrowhead) angle (dotted line) in F0 mutants. (D′) Quantification of the ceratohyal angle in bptf F0 CRISPR mutants (p ≤ 0.0001, n = 47–59 larvae/batch, repeated). Error bars indicate standard error of the mean (SEM). The American Journal of Human Genetics 2017 101, 503-515DOI: (10.1016/j.ajhg.2017.08.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Analysis of the 17q24.2 Microdeletion Region (A) Deletions in affected individuals reported previously39 and in this study. (B) Phenotype comparison of PSMD12-39 and BPTF-related disorders. Individuals with deletions affecting both genes are expected to have blended phenotypes. The American Journal of Human Genetics 2017 101, 503-515DOI: (10.1016/j.ajhg.2017.08.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions