Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli,

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Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis Francesca Mattioli, Elise Schaefer, Alex Magee, Paul Mark, Grazia M. Mancini, Klaus Dieterich, Gretchen Von Allmen, Marielle Alders, Charles Coutton, Marjon van Slegtenhorst, Gaëlle Vieville, Mark Engelen, Jan Maarten Cobben, Jane Juusola, Aurora Pujol, Jean-Louis Mandel, Amélie Piton The American Journal of Human Genetics Volume 100, Issue 1, Pages 105-116 (January 2017) DOI: 10.1016/j.ajhg.2016.11.010 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of a Co-segregating 2 bp Deletion, c.1052_1053del, in BRPF1 in a Family with Three Generations Affected by a Form of Mild ID Associated with Ptosis (A) Pedigree of family A, which has three affected generations. (B) The mutation partially escapes NMD. Quantitative real-time PCR was performed on RNA extracted (three extractions per individual) from fibroblasts of individual II-5 and three unrelated control individuals. The expression of BRPF1 in relation to the average of two reference genes, GAPDH and 18S, was calculated by the 2−ΔΔCt method. A t test was performed and showed no significant difference in the BRPF1 mRNA level (error bars indicate the SD of three independent experiments). Sequences of blood DNA and fibroblast cDNA (treated or not with the NMD-blocker emetine) from individual II.5 are shown on the right. (C) Expression of BRPF1 in HeLa cells. HeLa cells transfected with HA-tagged wild-type or p.Val351Glyfs∗8 BRPF1 cDNA. Cells were harvested 36 hr after transfection. BRPF1 expression was analyzed by SDS-PAGE, and immunoblotting was performed with anti-HA antibody. (D) HeLa cells were transfected with HA-tagged wild-type or p.Val351Glyfs∗8 BRPF1 cDNA. BRPF1 localization was visualized by immunofluorescence with an anti-HA antibody. Nuclei were colored in blue by Hoechst staining. (E) HA-tagged wild-type or mutant BRPF1 was transfected along with expression plasmids for FLAG-tagged KAT6A, HA-tagged ING5, and HA-tagged MEAF6 into HEK293 cells. HAT complexes were immunoprecipitated from protein extracts with anti-FLAG antibody to pull down KAT6A, and products of the complex were revealed by western blot using anti-HA antibody. The American Journal of Human Genetics 2017 100, 105-116DOI: (10.1016/j.ajhg.2016.11.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Mutations in BRPF1 and Deletions in the 3p25 Region (A) Overview of 3p25 deletions reported in the literature and in DECIPHER (from the UCSC Genome Browser). Black lines indicate a deletion encompassing both SETD5 and BRPF1; orange lines represent the deletion containing SETD5 but not BRPF1; and red lines indicate the two deletions including BRPF1 but not SETD5 reported in DECIPHER. (B) Pedigree of the two additional families affected by 3p25 deletions encompassing BRPF1 but not SETD5. (C) Pedigree of four additional families with the BRPF1 pathogenic variants shown in (D). (D) Top: schematic representation of BRPF1 and localization of the five different LoF and missense mutations. Bottom: the four de novo LoF variants described by the DDD project in individuals with neurodevelopmental conditions10 (in dark blue) and the LoF variant identified in one boy with schizophrenia and mild ID.11 Domains are colored as follows: yellow, PHD finger (PHD) domains; green, bromodomain (Bromo), involved in the recognition of acetylated lysine residues; blue, PWWP nucleosome-binding domain. Regions involved in binding with MOZ, MORF, ING5, and EAF6 are underlined.12 The American Journal of Human Genetics 2017 100, 105-116DOI: (10.1016/j.ajhg.2016.11.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Facial Characteristics of the Individuals with BRPF1 Mutations Pictures of individuals with BRPF1 point mutations and deletions. Common features include a roundish face, blepharophimosis and ptosis, downslanted palpebral fissures, temporal narrowing, and a downturned mouth. Ethical approval was obtained from the local ethics committees. For all individuals included in this figure, families also gave consent for publication of the images. The American Journal of Human Genetics 2017 100, 105-116DOI: (10.1016/j.ajhg.2016.11.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions