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

Publication ,  Journal Article
Castilla-Vallmanya, L; Selmer, KK; Dimartino, C; Rabionet, R; Blanco-Sánchez, B; Yang, S; Reijnders, MRF; van Essen, AJ; Oufadem, M; Stadheim, B ...
Published in: Genet Med
July 2020

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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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

July 2020

Volume

22

Issue

7

Start / End Page

1215 / 1226

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Transcriptome
  • Phenotype
  • Mutation, Missense
  • Intellectual Disability
  • Humans
  • Germ Cells
  • Genetics & Heredity
  • Exome
  • 3105 Genetics
 

Citation

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Castilla-Vallmanya, L., Selmer, K. K., Dimartino, C., Rabionet, R., Blanco-Sánchez, B., Yang, S., … Gordon, C. T. (2020). Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. Genet Med, 22(7), 1215–1226. https://doi.org/10.1038/s41436-020-0792-7
Castilla-Vallmanya, Laura, Kaja K. Selmer, Clémantine Dimartino, Raquel Rabionet, Bernardo Blanco-Sánchez, Sandra Yang, Margot R. F. Reijnders, et al. “Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.Genet Med 22, no. 7 (July 2020): 1215–26. https://doi.org/10.1038/s41436-020-0792-7.
Castilla-Vallmanya L, Selmer KK, Dimartino C, Rabionet R, Blanco-Sánchez B, Yang S, et al. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. Genet Med. 2020 Jul;22(7):1215–26.
Castilla-Vallmanya, Laura, et al. “Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.Genet Med, vol. 22, no. 7, July 2020, pp. 1215–26. Pubmed, doi:10.1038/s41436-020-0792-7.
Castilla-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 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-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, Undiagnosed Diseases Network, Care4Rare Canada Consortium, 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, Morel Swols D, 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. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. Genet Med. 2020 Jul;22(7):1215–1226.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

July 2020

Volume

22

Issue

7

Start / End Page

1215 / 1226

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Transcriptome
  • Phenotype
  • Mutation, Missense
  • Intellectual Disability
  • Humans
  • Germ Cells
  • Genetics & Heredity
  • Exome
  • 3105 Genetics