Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia Asli Sirmaci, Michail Spiliopoulos,

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Mutations in ANKRD11 Cause KBG Syndrome, Characterized by Intellectual Disability, Skeletal Malformations, and Macrodontia Asli Sirmaci, Michail Spiliopoulos, Francesco Brancati, Eric Powell, Duygu Duman, Alex Abrams, Guney Bademci, Emanuele Agolini, Shengru Guo, Berrin Konuk, Asli Kavaz, Susan Blanton, Maria Christina Digilio, Bruno Dallapiccola, Juan Young, Stephan Zuchner, Mustafa Tekin The American Journal of Human Genetics Volume 89, Issue 2, Pages 289-294 (August 2011) DOI: 10.1016/j.ajhg.2011.06.007 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Features of KBG Syndrome Written consents were obtained from all participants for publication of clinical images. Distinct facial features of KBG syndrome include a triangular face, low anterior and posterior hairlines, synophrys, hypertelorism, eyelid ptosis, a broad and high nasal bridge, an upturned nose, a long philtrum, and wide permanent central incisors (≥10 mm in males and ≥9.7 mm in females). Hand anomalies include brachydactyly, clinodactyly, and cutaneous syndactyly. Photographs were taken when individuals in family 1 were 25 years old (II-1), 22 years old (II-2), and 46 years old (I-1) and individual 1 in family 2 was 9 years old. Facial and dental pictures were taken when individual 1 in family 3 was 6 and 11 years old, respectively. Individual 1 in family 4 was 21 years old and individual 1 in family 5 was 9 years old when photographs were taken. The American Journal of Human Genetics 2011 89, 289-294DOI: (10.1016/j.ajhg.2011.06.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 ANKRD1 Mutations (A) Sanger results of identified mutations. Affected residues are underlined or indicated with arrows. (B) Quantitative PCR results of ANKRD11 in individual 1 of family 2 with a heterozygous c.2305delT mutation (left) and his unaffected father with homozygous wild-type alleles (right). (C) Sanger sequencing of ANKRD11 cDNA showing a heterozygous c.7570-1G>C mutation in individual II-1 in family 1. The deleted six base pairs correspond to two amino acids (red). (D) The alignment of a region from the C-terminal repression domain of ANKRD11 showing the localization of deleted amino acids (E and K) in family 1 as well as the mutation site in Yoda mice. The American Journal of Human Genetics 2011 89, 289-294DOI: (10.1016/j.ajhg.2011.06.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 ANKRD11 Domains and Identified Mutations The positions of the five identified mutations in ANKRD11 domains. The two mutations identified with exome sequencing are shown with blue characters. The American Journal of Human Genetics 2011 89, 289-294DOI: (10.1016/j.ajhg.2011.06.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Activity-Dependent Nuclear Aggregation of ANKRD11 (A) RT-PCR expression analysis of ANKRD11 in adult human brain cDNA. (1) DNA control sample, (2) cDNA sample with reverse transcriptase, and (3) cDNA sample without reverse transcriptase in RT reaction. (B) Representative image of neonatal cortical neurons transfected with GFP-ANKRD11 along with DsRed-MECP2. Postnatal day 1 neurons (cultured in vitro for 5 days) were cotransfected with GFP-ANKRD11 and Ds-Red-MECP2. Twenty-four hours after transfection, 50 mM KCl (or 5mM to controls plates) was added to the culture media for 90 min, cells were fixed, stained with antibodies to tyrosinated tubulin (blue), and imaged on a confocal microscope. (C) Higher magnification image of cotransfected neurons to observe GFP-ANKRD11 nuclear inclusions (arrows). GFP-ANKRD11 (green) and DsRed-MeCP2 (red) nuclear aggregates do not colocalize. (D) Representative glial cells (identified by their lack of tyrosinated-tubulin staining) from the same cultures as in (B). Note that in glial cells, ANKRD11 nuclear inclusions form regardless of KCl addition. The American Journal of Human Genetics 2011 89, 289-294DOI: (10.1016/j.ajhg.2011.06.007) Copyright © 2011 The American Society of Human Genetics Terms and Conditions