TY - JOUR
T1 - Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7
AU - Undiagnosed Diseases Network, Care4Rare Canada Consortium
AU - Castilla-Vallmanya, Laura
AU - Selmer, Kaja K.
AU - Dimartino, Clémantine
AU - Rabionet, Raquel
AU - Blanco-Sánchez, Bernardo
AU - Yang, Sandra
AU - Reijnders, Margot R.F.
AU - van Essen, Antonie J.
AU - Oufadem, Myriam
AU - Vigeland, Magnus D.
AU - Stadheim, Barbro
AU - Houge, Gunnar
AU - Cox, Helen
AU - Kingston, Helen
AU - Clayton-Smith, Jill
AU - Innis, Jeffrey W.
AU - Iascone, Maria
AU - Cereda, Anna
AU - Gabbiadini, Sara
AU - Chung, Wendy K.
AU - Sanders, Victoria
AU - Charrow, Joel
AU - Bryant, Emily
AU - Millichap, John
AU - Vitobello, Antonio
AU - Thauvin, Christel
AU - Mau-Them, Frederic Tran
AU - Faivre, Laurence
AU - Lesca, Gaetan
AU - Labalme, Audrey
AU - Rougeot, Christelle
AU - Chatron, Nicolas
AU - Sanlaville, Damien
AU - Christensen, Katherine M.
AU - Kirby, Amelia
AU - Lewandowski, Raymond
AU - Gannaway, Rachel
AU - Aly, Maha
AU - Lehman, Anna
AU - Clarke, Lorne
AU - Graul-Neumann, Luitgard
AU - Zweier, Christiane
AU - Lessel, Davor
AU - Lozic, Bernarda
AU - Aukrust, Ingvild
AU - Peretz, Ryan
AU - Stratton, Robert
AU - Smol, Thomas
AU - Dieux-Coëslier, Anne
AU - Sobreira, Nara
N1 - Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - TRAF7
KW - blepharophimosis
KW - craniofacial development
KW - intellectual disability
KW - patent ductus arteriosus
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U2 - 10.1038/s41436-020-0792-7
DO - 10.1038/s41436-020-0792-7
M3 - Article
C2 - 32376980
AN - SCOPUS:85085138268
SN - 1098-3600
VL - 22
SP - 1215
EP - 1226
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -