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

Genet Med
Authors
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.

Year of Publication
2020
Journal
Genet Med
Date Published
2020 May 07
ISSN
1530-0366
DOI
10.1038/s41436-020-0792-7
PubMed ID
32376980
Links
Grant list
CranioRespiro / Agence Nationale de la Recherche (FR)
CranioRespiro / Agence Nationale de la Recherche (FR)
CranioRespiro / Agence Nationale de la Recherche (FR)
CranioRespiro / Agence Nationale de la Recherche (FR)
U01HG009599 / HG / NHGRI NIH HHS / United States