Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Castilla-Vallmanya L, Selmer KK, Dimartino C, Rabionet R, Blanco-Sanchez 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 FT, Faivre L, Lesca G, Labalme A, Rougeot C, Chatron N, Sanlaville D, Christensen KM, 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-Coeslier 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 DM, Parisot M, Bole-Feysot C, Nitschke P, Pingault V, Munnich A, Cho MT, Cormier-Daire V, Balcells S, Lyonnet S, Grinberg D, Amiel J, Urreizti R, Gordon CT (2020)

Publication Type: Journal article

Publication year: 2020


DOI: 10.1038/s41436-020-0792-7


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.

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ASST Papa Giovanni XXIII IT Italy (IT) Institut des maladies génétiques Imagine FR France (FR) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Centre hospitalier universitaire (CHU) de Dijon Bourgogne FR France (FR) Central Manchester University Hospitals GB United Kingdom (GB) Ann & Robert H. Lurie Children's Hospital of Chicago US United States (USA) (US) Université de Bourgogne (uB) / University of Burgundy / University of Dijon FR France (FR) Hôpital Femme Mère Enfant FR France (FR) Columbia University US United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet NO Norway (NO) University of California Santa Cruz US United States (USA) (US) Duke University US United States (USA) (US) University of California San Francisco (UCSF) US United States (USA) (US) Massachusetts General Hospital US United States (USA) (US) Murdoch Childrens Research Institute AU Australia (AU) Charité - Universitätsmedizin Berlin DE Germany (DE) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) Hospices Civils de Lyon (CHU) FR France (FR) University of Michigan US United States (USA) (US) University Hospital Split HR Croatia (HR) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) FR France (FR) Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) Washington University in St. Louis US United States (USA) (US) Driscoll Children's Hospital US United States (USA) (US) Johns Hopkins University (JHU) US United States (USA) (US) University of British Columbia CA Canada (CA) Western University CA Canada (CA) Royal Children's Hospital Parkville AU Australia (AU) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen NL Netherlands (NL) Mercy Kids Genetics US United States (USA) (US) Emory University US United States (USA) (US) GeneDX US United States (USA) (US) Université Sorbonne Paris Cité FR France (FR) Saint Louis University (SLU) US United States (USA) (US) Virginia Commonwealth University (VCU) US United States (USA) (US) University of Bologna / Università di Bologna IT Italy (IT) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Seattle Children's Hospital US United States (USA) (US) University of Oslo NO Norway (NO) Universitat de Barcelona (UB) / University of Barcelona ES Spain (ES) University of Miami US United States (USA) (US) Universidade Federal da Bahia BR Brazil (BR) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore IT Italy (IT) Maastricht University NL Netherlands (NL) Northwestern University US United States (USA) (US) Miami Children's Hospital US United States (USA) (US)

How to cite


Castilla-Vallmanya, L., Selmer, K.K., Dimartino, C., Rabionet, R., Blanco-Sanchez, B., Yang, S.,... Gordon, C.T. (2020). Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. Genetics in Medicine.


Castilla-Vallmanya, Laura, et al. "Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7." Genetics in Medicine (2020).

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