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) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10) 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.

Genetic Diversity and Selection Signatures Within Diannan Small-Ear Pigs Revealed by Next-Generation Sequencing

“…In addition, PALM2-AKAP2 was a potential locus associated with height according to the previous GWAS for the Korean population (Kim et al, 2010). Both biallelic deleterious mutations in NANS and de novo missense variants in TRAF7 have been reported to be associated with developmental delay or severe skeletal dysplasia (van Karnebeek et al, 2016;Tokita et al, 2018). PACSIN1 was also detected as a causal gene for body weight in Meishan pigs (Sun et al, 2018).…”

Recurrent de novo MAPK8IP3 variants cause neurological phenotypes

“…We identified 4 unrelated individuals in a total of approximately 2,450 individuals in an undiagnosed exome cohort in our three institutions. The likelihood of de novo variants in the same residue, c.1732C>T (p.Arg578Cys) or c.3436C>T (p.Arg1146Cys), in MAPK8IP3 in 2 unrelated individuals was calculated to be 2.56 × 10 –9 , using the Poisson model as previously described . This finding remained significant when we corrected for the 18,892 genes targeted in the Consensus Coding Sequence (CCDS release 20; p = 4.83 × 10 –5 ).…”

Genetic Alterations of TRAF Proteins in Human Cancers

“…Importantly however, Tokita et al recently reported that de novo missense mutations in TRAF7 cause developmental abnormalities and other clinical symptoms in seven unrelated patients, including developmental delay (5/5), congenital heart defects (6/7), limb and digital anomalies (7/7), and dysmorphic facial features (7/7) ( 300 ). TRAF7 mutations identified in this study include a recurrent R655Q mutation found in four patients, and another 3 single mutations each identified in one patient, including K346E, R371G, and T601A ( 300 ). Interestingly, R371 recurrent mutations are also detected in human cancers (Figure 3 ).…”

“…Both T601 and R665 are located in the C-terminal WD40 repeats of TRAF7, which contain most mutation hotspots of TRAF7 detected in human cancers (Figure 3 ) and are known to mediate the interaction of TRAF7 with MEKK3 or c-Myb ( 302 , 305 ). Tokita et al further revealed that transfection of the R665Q, T601A, or R371G mutants of TRAF7 into HEK293T cells results in significantly reduced levels of ERK1/2 phosphorylation, both basal and in response to TNFα signaling ( 300 ). Consistent with this biochemical evidence, conditional ERK2 −/− mice show a phenotype mirroring that observed in the seven patients with TRAF7 mutations, including craniofacial abnormalities, cardiovascular malformations and limb defects ( 306 ).…”