|Title||Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Castilla-Vallmanya, L, Selmer, KK, Dimartino, C, Rabionet, R, Blanco-Sánchez, B, Yang, S, Reijnders, MRF, van Essen, AJ, Oufadem, M, Vigeland, MD, Stadheim, B, Houge, G, Cox, H, Kingston, H, Clayton-Smith, J, Innis, JW, Iascone, M, Cereda, A, Gabbiadini, S, Chung, WK, Sanders, V, Charrow, J, Bryant, E, Millichap, J, Vitobello, A, Thauvin, C, Mau-Them, FTran, Faivre, L, Lesca, G, Labalme, A, Rougeot, C, Chatron, N, Sanlaville, D, Christensen, KM, Kirby, A, Lewandowski, R, Gannaway, R, Aly, MAH, Lehman, A, Clarke, L, Graul-Neumann, L, Zweier, C, Lessel, D, Lozic, B, Aukrust, I, Peretz, R, Stratton, R, Smol, T, Dieux-Coëslier, A, Meira, J, Wohler, E, Sobreira, N, Beaver, EM, Heeley, J, Briere, LC, High, FA, Sweetser, DA, Walker, MA, Keegan, CE, Jayakar, P, Shinawi, M, Kerstjens-Frederikse, WS, Earl, DL, Siu, VM, Reesor, E, Yao, T, Hegele, RA, Vaske, OM, Rego, S, Shapiro, KA, Wong, B, Gambello, MJ, McDonald, M, Karlowicz, D, Colombo, R, Serretti, A, Pais, L, O'Donnell-Luria, A, Wray, A, Sadedin, S, Chong, B, Tan, TY, Christodoulou, J, White, SM, Slavotinek, A, Barbouth, D, Swols, DMorel, Parisot, M, Bole-Feysot, C, Nitschké, P, Pingault, V, Munnich, A, Cho, MT, Cormier-Daire, V, Balcells, S, Lyonnet, S, Grinberg, D, Amiel, J, Urreizti, R, Gordon, CT|
|Corporate Authors||Undiagnosed Diseases Network, Care4Rare Canada Consortium|
|Date Published||2020 07|
|Keywords||Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins|
PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.
METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.
RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.
CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC8093014|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States |
U01 HG009599 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U01HG009599 / HG / NHGRI NIH HHS / United States
P50 HD103538 / HD / NICHD NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States