Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Undiagnosed Diseases Network, Care4Rare Canada Consortium

doi:10.1038/s41436-020-0792-7

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Undiagnosed Diseases Network, Care4Rare Canada Consortium

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1215-1226
Number of pages	12
Journal	Genetics in Medicine
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/s41436-020-0792-7
State	Published - Jul 1 2020

Funding

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 Innovación (SAF2016-75946R), CIBERER (ACCI2018-15), Associació Síndrome 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’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.

Keywords

TRAF7
blepharophimosis
craniofacial development
intellectual disability
patent ductus arteriosus

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-020-0792-7

Cite this

@article{e36da8e84cec4c2fa431337657636b02,

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 = "TRAF7, blepharophimosis, craniofacial development, intellectual disability, patent ductus arteriosus",

author = "{Undiagnosed Diseases Network, Care4Rare Canada Consortium} and Laura Castilla-Vallmanya and Selmer, {Kaja K.} and Cl{\'e}mantine Dimartino and Raquel Rabionet and Bernardo Blanco-S{\'a}nchez and Sandra Yang and Reijnders, {Margot R.F.} and {van Essen}, {Antonie J.} and Myriam Oufadem and Vigeland, {Magnus D.} and Barbro Stadheim and Gunnar Houge and Helen Cox and Helen Kingston and Jill Clayton-Smith and Innis, {Jeffrey W.} and Maria Iascone and Anna Cereda and Sara Gabbiadini and Chung, {Wendy K.} and Victoria Sanders and Joel Charrow and Emily Bryant and John Millichap and Antonio Vitobello and Christel Thauvin and Mau-Them, {Frederic Tran} and Laurence Faivre and Gaetan Lesca and Audrey Labalme and Christelle Rougeot and Nicolas Chatron and Damien Sanlaville and Christensen, {Katherine M.} and Amelia Kirby and Raymond Lewandowski and Rachel Gannaway and Maha Aly and Anna Lehman and Lorne Clarke and Luitgard Graul-Neumann and Christiane Zweier and Davor Lessel and Bernarda Lozic and Ingvild Aukrust and Ryan Peretz and Robert Stratton and Thomas Smol and Anne Dieux-Co{\"e}slier and Joanna Meira",

note = "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 (US)",

volume = "22",

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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 - Meira, Joanna

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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SN - 1098-3600

VL - 22

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JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 7

ER -

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Abstract

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Keywords

ASJC Scopus subject areas

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