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

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

Author information

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: yapingy@bcm.edu.
17
Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: xiaw@bcm.edu.

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

PMID:
29961569
PMCID:
PMC6035372
[Available on 2019-01-05]
DOI:
10.1016/j.ajhg.2018.06.005

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