Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

L. Castilla-Vallmanya, K.K. Selmer, C. Dimartino, R. Rabionet, B. Blanco-Sanchez, S. Yang, M.R.F. Reijnders, A.J. van Essen, M. Oufadem, M.D. Vigeland, B. Stadheim, G. Houge, H. Cox, H. Kingston, J. Clayton-Smith, J.W. Innis, M. Iascone, A. Cereda, S. Gabbiadini, W.K. ChungV. Sanders, J. Charrow, E. Bryant, J. Millichap, A. Vitobello, C. Thauvin, F.T. Mau-Them, L. Faivre, G. Lesca, A. Labalme, C. Rougeot, N. Chatron, D. Sanlaville, K.M. Christensen, A. Kirby, R. Lewandowski, R. Gannaway, M. Aly, A. Lehman, L. Clarke, L. Graul-Neumann, C. Zweier, D. Lessel, B. Lozic, I. Aukrust, R. Peretz, R. Stratton, T. Smol, A. Dieux-Coeslier, J. Meira, Care4Rare Canada Consortium, Undiagnosed Diseases Network, Christopher T. Gordon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1215-1226
Number of pages12
JournalGenetics in Medicine
Issue number7
Publication statusPublished - 1 Jul 2020


  • activation
  • akt1
  • blepharophimosis
  • craniofacial development
  • genomic analysis
  • intellectual disability
  • leads
  • meningiomas
  • mutations
  • nf-kappa-b
  • patent ductus arteriosus
  • polyubiquitination
  • protein
  • target
  • traf7
  • AKT1
  • TRAF7

Cite this