Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Undiagnosed Diseases Network, Care4Rare Canada Consortium, Castilla-Vallmanya, L., Selmer, K. K., Dimartino, C., Rabionet, R., Blanco-Sánchez, B., Yang, S., Reijnders, M. R. F., van Essen, A. J., Oufadem, M., Vigeland, M. D., Stadheim, B., Houge, G., Cox, H., Kingston, H., Clayton-Smith, J., Innis, J. W., Iascone, M., Cereda, A., Gabbiadini, S., Chung, W. K., Sanders, V., Charrow, J., Bryant, E., Millichap, J., Vitobello, A., Thauvin, C., Mau-Them, F. T., Faivre, L., Lesca, G., Labalme, A., Rougeot, C., Chatron, N., Sanlaville, D., Christensen, K. M., Kirby, A., Lewandowski, R., Gannaway, R., Aly, M., 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. L., Beaver, E. M., Heeley, J. M., Briere, L. C., High, F. A., Sweetser, D. A., Walker, M. A., Keegan, C. E., Jayaker, P., Shinawi, M., Kerstjens, M., Earl, D. L., Siu, V. M., Reesor, E., Yao, T., Hegele, R. A., Vaske, O. M., Rego, S., Shapiro, K. A., Wong, B., Gambello, M. J., McDonald, M. T., Karlowicz, D., Colombo, R., Serretti, A., Pais, L., O’Donnell-Luria, A., Wray, A., Sadedin, S., Chong, B., Tan, T. Y., Christodoulou, J., White, S. M., Slavotinek, A., Barbouth, D., Morel Swols, D., Parisot, M., Bole-Feysot, C., Nitschke, P., Pingault, V., Munnich, A., Cho, M. T., Cormier-Daire, V., Balcells, S., Lyonnet, S., Grinberg, D., Amiel, J., Urreizti, R. & Gordon, C. T., 7-May-2020, In : Genetics in Medicine. p. 1215-1226 12 p.

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  • Phenotypic spectrum and transcriptomic profile associated

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  • Undiagnosed Diseases Network, Care4Rare Canada Consortium
  • Laura Castilla-Vallmanya
  • Kaja K Selmer
  • Clémantine Dimartino
  • Raquel Rabionet
  • Bernardo Blanco-Sánchez
  • Sandra Yang
  • Margot R F Reijnders
  • Antonie J van Essen
  • Myriam Oufadem
  • Magnus D Vigeland
  • Barbro Stadheim
  • Gunnar Houge
  • Helen Cox
  • Helen Kingston
  • Jill Clayton-Smith
  • Jeffrey W Innis
  • Maria Iascone
  • Anna Cereda
  • Sara Gabbiadini
  • Wendy K Chung
  • Victoria Sanders
  • Joel Charrow
  • Emily Bryant
  • John Millichap
  • Antonio Vitobello
  • Christel Thauvin
  • Frederic Tran Mau-Them
  • Laurence Faivre
  • Gaetan Lesca
  • Audrey Labalme
  • Christelle Rougeot
  • Nicolas Chatron
  • Damien Sanlaville
  • Katherine M Christensen
  • Amelia Kirby
  • Raymond Lewandowski
  • Rachel Gannaway
  • Maha Aly
  • Anna Lehman
  • Lorne Clarke
  • Luitgard Graul-Neumann
  • Christiane Zweier
  • Davor Lessel
  • Bernarda Lozic
  • Ingvild Aukrust
  • Ryan Peretz
  • Robert Stratton
  • Thomas Smol
  • Anne Dieux-Coëslier
  • Joanna Meira
  • Elizabeth Wohler
  • Nara L. Sobreira
  • Erin M. Beaver
  • Jennifer M. Heeley
  • Lauren C. Briere
  • Frances A. High
  • David A Sweetser
  • Melissa A. Walker
  • Catherine E. Keegan
  • Paul Jayaker
  • Marwan Shinawi
  • Mieke Kerstjens
  • Dawn L Earl
  • Victoria M. Siu
  • Emma Reesor
  • Tony Yao
  • Robert A. Hegele
  • Olena M. Vaske
  • Shannon Rego
  • Kevin A. Shapiro
  • Brian Wong
  • Michael J. Gambello
  • Marie T. McDonald
  • Danielle Karlowicz
  • Roberto Colombo
  • Alessandro Serretti
  • Lynn Pais
  • Anne O’Donnell-Luria
  • Alison Wray
  • Simon Sadedin
  • Belinda Chong
  • Tiong Y. Tan
  • John Christodoulou
  • Susan M White
  • Anne Slavotinek
  • Deborah Barbouth
  • Dayna Morel Swols
  • Mélanie Parisot
  • Christine Bole-Feysot
  • Patrick Nitschke
  • Véronique Pingault
  • Arnold Munnich
  • Megan T. Cho
  • Valérie Cormier-Daire
  • Susanna Balcells
  • Stanislas Lyonnet
  • Daniel Grinberg
  • Jeanne Amiel
  • Roser Urreizti
  • Christopher T. Gordon

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
Publication statusE-pub ahead of print - 7-May-2020


  • TRAF7, craniofacial development, intellectual disability, blepharophimosis, patent ductus arteriosus, NF-KAPPA-B, GENOMIC ANALYSIS, MUTATIONS, POLYUBIQUITINATION, MENINGIOMAS, ACTIVATION, PROTEIN, TARGET, LEADS, AKT1

ID: 124747976