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De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

ABSTRACT: TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

SUBMITTER: Tokita MJ

PROVIDER: S-EPMC6035372 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

Tokita Mari J MJ Chen Chun-An CA Chitayat David D Macnamara Ellen E Rosenfeld Jill A JA Hanchard Neil N Lewis Andrea M AM Brown Chester W CW Brown Chester W CW Marom Ronit R Shao Yunru Y Novacic Danica D Wolfe Lynne L Wahl Colleen C Tifft Cynthia J CJ Toro Camilo C Bernstein Jonathan A JA Hale Caitlin L CL Silver Julia J Hudgins Louanne L Ananth Amitha A Hanson-Kahn Andrea A Shuster Shirley S Magoulas Pilar L PL Patel Vipulkumar N VN Zhu Wenmiao W Chen Stella M SM Jiang Yanjun Y Liu Pengfei P Eng Christine M CM Batkovskyte Dominyka D di Ronza Alberto A Sardiello Marco M Lee Brendan H BH Schaaf Christian P CP Yang Yaping Y Wang Xia X

American journal of human genetics 20180628 1

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified var ...[more]

PMID: 29961569

Dataset Information

De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

Publications

De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

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