De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features Mari J. Tokita, Chun-An Chen, David Chitayat,

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De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features Mari J. Tokita, Chun-An Chen, David Chitayat, Ellen Macnamara, Jill A. Rosenfeld, Neil Hanchard, Andrea M. Lewis, Chester W. Brown, Ronit Marom, Yunru Shao, Danica Novacic, Lynne Wolfe, Colleen Wahl, Cynthia J. Tifft, Camilo Toro, Jonathan A. Bernstein, Caitlin L. Hale, Julia Silver, Louanne Hudgins, Amitha Ananth, Andrea Hanson-Kahn, Shirley Shuster, Pilar L. Magoulas, Vipulkumar N. Patel, Wenmiao Zhu, Stella M. Chen, Yanjun Jiang, Pengfei Liu, Christine M. Eng, Dominyka Batkovskyte, Alberto di Ronza, Marco Sardiello, Brendan H. Lee, Christian P. Schaaf, Yaping Yang, Xia Wang The American Journal of Human Genetics Volume 103, Issue 1, Pages 154-162 (July 2018) DOI: 10.1016/j.ajhg.2018.06.005 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Facial Features and Limb Phenotypes for Subjects with TRAF7 Variants Shown are subject 7 (A), subject 4 (B), subject 3 (C), subject 5 (D), subject 6 (E), and subject 1 (F). Shared dysmorphic features included epicanthal folds, ptosis, abnormally set or dysplastic ears, a low hairline, excess nuchal skin, and multiple hair whorls. Overlapping toes are shown in (C) and (F). The American Journal of Human Genetics 2018 103, 154-162DOI: (10.1016/j.ajhg.2018.06.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 In Silico Analysis of the Four TRAF7 Variants Identified in This Study (A) The R655, T601, R371, and K346 residues are conserved from human to zebrafish (prepared from UCSC genome browser Multiz Alignments of 100 Vertebrates track). (B) Schematic view of the TRAF7 exon-intron structure. Blue boxes represent exons and yellow fields represent introns. The identified cDNA changes are listed. (C) Schematic view of the TRAF7 protein and its domains based on data extracted from Zotti et al.7 Domains are represented by blue shapes. The domain names and the identified amino acid changes are listed. The American Journal of Human Genetics 2018 103, 154-162DOI: (10.1016/j.ajhg.2018.06.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 The Effect of TRAF7 Mutants on ERK1/2 Signaling (A) Phosphorylation of ERK1/2 was analyzed by transiently expressing the FLAG-tagged wild-type and mutant constructs in HEK293T cells. Twenty-four hours after transfection, cells were stimulated with 10 ng ml−1 TNFα for 30 min. Cells were then collected and lysed and immunoblotting was performed. Expression of the TRAF7 mutants resulted in decreased phosphorylation of ERK1/2 when compared with cells expressing wild-type protein, either with or without TNFα treatment. Asterisk and pound symbols indicate ERK1 and ERK2, respectively. (B–E) Quantification of the effect of TRAF7 mutants on ERK1/2 signaling. pERK1 (B) and pERK2 (C) signaling without TNFα treatment. pERK1 (D) and pERK2 (E) signaling with 10 ng ml−1 TNFα stimulation for 30 min. All data were normalized to GAPDH protein levels, with the wild-type protein set at 1.0. The results are representative of three independent experiments. ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗∗∗p ≤ 0.0001, one-way ANOVA with Dunnett’s multiple-comparisons test. Data were shown as mean ± standard error of the mean, n = 3. The American Journal of Human Genetics 2018 103, 154-162DOI: (10.1016/j.ajhg.2018.06.005) Copyright © 2018 American Society of Human Genetics Terms and Conditions