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

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.
Mari J Tokita 1,  Chun-An Chen 2,  David Chitayat 3,  Ellen Macnamara 4,  Jill A Rosenfeld 1,  Neil Hanchard 5,  Andrea M Lewis 5,  Chester W Brown 6,  Ronit Marom 5,  Yunru Shao 5,  Danica Novacic 7,  Lynne Wolfe 7,  Colleen Wahl 4,  Cynthia J Tifft 4,  Camilo Toro 4,  Jonathan A Bernstein 8,  Caitlin L Hale 9,  Julia Silver 10,  Louanne Hudgins 8,  Amitha Ananth 11,  Andrea Hanson-Kahn 12,  Shirley Shuster 3,  Undiagnosed Diseases Network,  Pilar L Magoulas 5,  Vipulkumar N Patel 13,  Wenmiao Zhu 13,  Stella M Chen 13,  Yanjun Jiang 13,  Pengfei Liu 14,  Christine M Eng 14,  Dominyka Batkovskyte 1,  Alberto di Ronza 1,  Marco Sardiello 1,  Brendan H Lee 1,  Christian P Schaaf 15,  Yaping Yang 16,  Xia Wang 17
Affiliations

Affiliations

  • 1 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 3 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada.
  • 4 NIH Undiagnosed Diseases Program, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 6 University of Tennessee Health Science Center, Memphis, TN 38163, USA; Le Bonheur Children's Hospital, Memphis, TN 38103, USA.
  • 7 NIH Undiagnosed Diseases Program, National Institutes of Health, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD 20892, USA.
  • 8 Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 9 Lucile Packard Children's Hospital Stanford, Stanford, CA 94305, USA.
  • 10 Prenatal Diagnostic Center, University of California San Francisco, San Francisco, CA 94158, USA.
  • 11 University of Alabama, Birmingham, AL 35294, USA.
  • 12 Stanford University School of Medicine, Stanford, CA 94305, USA; Lucile Packard Children's Hospital Stanford, Stanford, CA 94305, USA.
  • 13 Baylor Genetics, Houston, TX 77021, USA.
  • 14 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
  • 15 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Human Genetics, University Hospital Cologne, Cologne 50931, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany; Center for Rare Diseases, University Hospital Cologne, Cologne 50931, Germany; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 16 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: [email protected].
  • 17 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: [email protected].
PMID: 29961569 DOI: 10.1016/j.ajhg.2018.06.005
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.

Keywords

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

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