@article{219e6f2d7e0041f9b48c41e6857f0ee8,
title = "Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7",
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.",
keywords = "activation, akt1, blepharophimosis, craniofacial development, genomic analysis, intellectual disability, leads, meningiomas, mutations, nf-kappa-b, patent ductus arteriosus, polyubiquitination, protein, target, traf7, TARGET, ACTIVATION, PROTEIN, GENOMIC ANALYSIS, MENINGIOMAS, AKT1, MUTATIONS, POLYUBIQUITINATION, NF-KAPPA-B, TRAF7, LEADS",
author = "L. Castilla-Vallmanya and K.K. Selmer and C. Dimartino and R. Rabionet and B. Blanco-Sanchez and S. Yang and M.R.F. Reijnders and {van Essen}, A.J. and M. Oufadem and M.D. Vigeland and B. Stadheim and G. Houge and H. Cox and H. Kingston and J. Clayton-Smith and J.W. Innis and M. Iascone and A. Cereda and S. Gabbiadini and W.K. Chung and V. Sanders and J. Charrow and E. Bryant and J. Millichap and A. Vitobello and C. Thauvin and F.T. Mau-Them and L. Faivre and G. Lesca and A. Labalme and C. Rougeot and N. Chatron and D. Sanlaville and K.M. Christensen and A. Kirby and R. Lewandowski and R. Gannaway and M. Aly and A. Lehman and L. Clarke and L. Graul-Neumann and C. Zweier and D. Lessel and B. Lozic and I. Aukrust and R. Peretz and R. Stratton and T. Smol and A. Dieux-Coeslier and J. Meira and {Care4Rare Canada Consortium} and {Undiagnosed Diseases Network} and Gordon, {Christopher T.}",
note = "Funding Information: We thank the families for their participation. This work was supported by the Agence Nationale de la Recherche (CranioR-espiro and ANR-10-IAHU-01), MSD Avenir (Devo-Decode), Spanish Ministerio de Ciencia e Innovaci{\'o}n (SAF2016-75946R), CIBERER (ACCI2018-15), Associaci{\'o} S{\'i}ndrome Opitz C, the Morton S. and Henrietta K. Sellner Professorship in Human Genetics (J.W.I.), JPB Foundation and the Simons Foundation SFARI program (W.K.C.), German Research Foundation (DFG; LE 4223/1; to D.L.), BC Children{\textquoteright}s Hospital Foundation and Genome BC (CAUSES Study), PG23/FROM 2017 Call for Independent Research as part of the Rapid Analysis for Rapid carE project (M.I., A.C.), the Victorian Government's Operational Infrastructure Support Program, the National Human Genome Research Institute (NHGRI) (UM1 HG008900, U01HG009599, UM1 HG006542), a National Institutes of Health (NIH) Common Fund grant (U01HG00769) and the Health Innovation Challenge Fund (DDD study; grant number HICF-1009-003). See Table S7 for supplementary acknowledgements. Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",
year = "2020",
month = jul,
day = "1",
doi = "10.1038/s41436-020-0792-7",
language = "English",
volume = "22",
pages = "1215--1226",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "7",
}