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

Am J Hum Genet. 2018 Jul 5;103(1):154-162. doi: 10.1016/j.ajhg.2018.06.005. Epub 2018 Jun 28.


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.

Keywords: ERK1/2; MAPKs; RASopathy; TRAF7; cancer; congenital heart defects; de novo missense variants; developmental delay; exome sequencing; limb and digit anomalies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acids / genetics
  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics*
  • Exome / genetics
  • Female
  • Heart Defects, Congenital / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability / genetics*
  • MAP Kinase Signaling System / genetics
  • Male
  • Musculoskeletal Abnormalities / genetics
  • Mutation, Missense / genetics*
  • Phenotype
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics*


  • Amino Acids
  • TRAF7 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins