Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

TitlePhenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
Publication TypeJournal Article
Year of Publication2020
AuthorsCastilla-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 AuthorsUndiagnosed Diseases Network, Care4Rare Canada Consortium
JournalGenet Med
Date Published2020 07
KeywordsExome, 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 JournalGenet Med
PubMed ID32376980
PubMed Central IDPMC8093014
Grant ListUM1 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