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

Journal

DOI: 10.1038/s41436-020-0792-7

Abstract

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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Involved external institutions

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

How to cite

APA:

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. https://dx.doi.org/10.1038/s41436-020-0792-7

MLA:

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

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