REPORT De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features Mari J. Tokita, 1,17 Chun-An Chen, 1,16,17 David Chitayat, 2 Ellen Macnamara, 3 Jill A. Rosenfeld, 1 Neil Hanchard, 1,4 Andrea M. Lewis, 1,4 Chester W. Brown, 5,6 Ronit Marom, 1,4 Yunru Shao, 1,4 Danica Novacic, 3,7 Lynne Wolfe, 3,7 Colleen Wahl, 3 Cynthia J. Tifft, 3 Camilo Toro, 3 Jonathan A. Bernstein, 8 Caitlin L. Hale, 9 Julia Silver, 10 Louanne Hudgins, 8 Amitha Ananth, 11 Andrea Hanson-Kahn, 8,9 Shirley Shuster, 2 Undiagnosed Diseases Network, Pilar L. Magoulas, 1,4 Vipulkumar N. Patel, 12 Wenmiao Zhu, 12 Stella M. Chen, 12 Yanjun Jiang, 12 Pengfei Liu, 1,12 Christine M. Eng, 1,12 Dominyka Batkovskyte, 1 Alberto di Ronza, 1 Marco Sardiello, 1 Brendan H. Lee, 1 Christian P. Schaaf, 1,13,14,15,16 Yaping Yang, 1,12,18, * and Xia Wang 1,12,18, * TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germ- line TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six indi- viduals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate anal- ysis showed that the occurrence of the de novo variants in TRAF7 (p ¼ 2.6 3 10 À3 ) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p ¼ 1.9 3 10 À8 ) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development. Somatic and germline mutations in proto-oncogenes and tumor suppressor genes are well-known causes of cancer. Many proto-oncogenes and tumor suppressor genes also play a crucial role in human development and as such, germline mutations in these genes can lead to develop- mental disorders. 1–6 TRAF7 (Tumor necrosis factor recep- tor-associated factor 7 [MIM: 606692]) belongs to the multi-functional TRAF family and is involved in multiple biological processes, including ubiquitination and myo- genesis. 7 TRAF7 is also a known mediator of the MAP kinase and NF-kB signaling pathways. 7 Somatic muta- tions in TRAF7 have been reported in meningioma and mesothelioma. 8 Although germline TRAF7 variants have been reported in two individuals with autism spec- trum disorder, 9,10 a clear association between germline defects in TRAF7 and human disease has not been established. Herein we report missense variants in TRAF7 in seven unrelated individuals with overlapping features. This study was performed according to the standards of the ethics committees and the institutional review boards at Baylor College of Medicine, the National Institutes of Health, and Stanford University. Written informed con- sent was obtained from all study participants. Medical re- cords were reviewed and clinical information was ex- tracted for phenotype analysis. Key clinical features are summarized in Table 1 and are discussed below; compre- hensive phenotype information is available in Table S1. Select photographs of the described subjects are presented in Figure 1. Clinical exome sequencing was performed as previously described; 11 sequencing metrics are summa- rized in Table S2. The study cohort consisted of two female and five male subjects ranging in age from 1 week to 43 years. Prenatal histories were notable for antenatal detection of heart anomalies (n ¼ 3), cystic hygroma (n ¼ 2), and two-vessel cord (n ¼ 2). Postnatally, several patients had respiratory distress (n ¼ 4) and poor feeding (n ¼ 3). Congenital heart 1 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; 2 The Prenatal Diagnosis and Medical Genetics Program, Depart- ment of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada; 3 NIH Undiagnosed Diseases Program, National Institutes of Health, Bethesda, MD 20892, USA; 4 Texas Children’s Hospital, Houston, TX 77030, USA; 5 University of Tennessee Health Science Center, Memphis, TN 38163, USA; 6 Le Bonheur Children’s Hospital, Memphis, TN 38103, USA; 7 Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD 20892, USA; 8 Stanford University School of Medicine, Stanford, CA 94305, USA; 9 Lucile Packard Children’s Hospital Stan- ford, Stanford, CA 94305, USA; 10 Prenatal Diagnostic Center, University of California San Francisco, San Francisco, CA 94158, USA; 11 University of Ala- bama, Birmingham, AL 35294, USA; 12 Baylor Genetics, Houston, TX 77021, USA; 13 Institute of Human Genetics, University Hospital Cologne, Cologne 50931, Germany; 14 Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany; 15 Center for Rare Diseases, University Hos- pital Cologne, Cologne 50931, Germany; 16 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA 17 These authors contributed equally to this work 18 These authors contributed equally to this work *Correspondence: yapingy@bcm.edu (Y.Y.), xiaw@bcm.edu (X.W.) https://doi.org/10.1016/j.ajhg.2018.06.005. 154 The American Journal of Human Genetics 103, 154–162, July 5, 2018 Ó 2018 American Society of Human Genetics.