Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

TY - JOUR

T1 - Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

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 - Meira, Joanna

AU - Wohler, Elizabeth

AU - Sobreira, Nara

AU - Beaver, Erin M

AU - Heeley, Jennifer

AU - Briere, Lauren C

AU - High, Frances A

AU - Sweetser, David A

AU - Walker, Melissa A

AU - Keegan, Catherine E

AU - Jayakar, Parul

AU - Shinawi, Marwan

AU - Kerstjens-Frederikse, Wilhelmina S

AU - Earl, Dawn L

AU - Siu, Victoria M

AU - Reesor, Emma

AU - Yao, Tony

AU - Hegele, Robert A

AU - Vaske, Olena M

AU - Rego, Shannon

AU - Shapiro, Kevin A

AU - Wong, Brian

AU - Gambello, Michael J

AU - McDonald, Marie

AU - Karlowicz, Danielle

AU - Colombo, Roberto

AU - Serretti, Alessandro

AU - Pais, Lynn

AU - O'Donnell-Luria, Anne

AU - Wray, Alison

AU - Sadedin, Simon

AU - Chong, Belinda

AU - Tan, Tiong Y

AU - Christodoulou, John

AU - White, Susan M

AU - Slavotinek, Anne

AU - Barbouth, Deborah

AU - Morel Swols, Dayna

AU - Parisot, Mélanie

AU - Bole-Feysot, Christine

AU - Nitschké, Patrick

AU - Pingault, Véronique

AU - Munnich, Arnold

AU - Cho, Megan T

AU - Cormier-Daire, Valérie

AU - Balcells, Susanna

AU - Lyonnet, Stanislas

AU - Grinberg, Daniel

AU - Amiel, Jeanne

AU - Urreizti, Roser

AU - Gordon, Christopher T

AU - Undiagnosed Diseases Network, Care4Rare Canada Consortium

PY - 2020/7

Y1 - 2020/7

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.

U2 - 10.1038/s41436-020-0792-7

DO - 10.1038/s41436-020-0792-7

M3 - SCORING: Journal article

C2 - 32376980

VL - 22

SP - 1215

EP - 1226

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 7

ER -