TRAF7 – cardiac, facial, and digital anomalies with developmental delay

The tumor necrosis factor receptor–associated factor 7 (TRAF7) gene is causally linked to a developmental malformation syndrome characterized by congenital cardiac defects, facial dysmorphism, digital anomalies, and global developmental delay (cardiac, facial, and digital anomalies with developmental delay).

Initial exome sequencing in seven unrelated individuals identified de novo heterozygous missense variants in TRAF7 affecting conserved WD40 repeats, with four patients harboring the recurrent c.1964G>A (p.Arg655Gln) variant (PMID:29961569).

A large-scale study of 45 additional patients confirmed the autosomal dominant inheritance of heterozygous missense mutations clustering in the C-terminal WD40 domain. All 45 exhibited a consistent clinical gestalt including blepharophimosis, short neck, pectus carinatum, digital deviations, and patent ductus arteriosus (PMID:32376980).

Two further unrelated cases brought the total to 54 probands, reinforcing the phenotype and variant spectrum of CAFDADD (PMID:34513876).

Functional characterization in patient-derived fibroblasts revealed that TRAF7 mutants disrupt NF-κB signaling, evidenced by reduced ERK1/2 phosphorylation and differential gene expression profiles compared to controls (PMID:29961569; PMID:32376980).

In vivo knockdown of TRAF7 in Xenopus and zebrafish recapitulates cardiac, craniofacial, and ciliary defects, demonstrating a dominant-negative mechanism via impaired TRAF7–IFT57 interactions and cilia degradation (PMID:37043537).

Collectively, the replication of de novo heterozygous TRAF7 missense variants in >50 unrelated individuals, recurrent hotspot mutations, and concordant functional and animal model data support a Definitive gene–disease relationship for TRAF7 in CAFDADD.

Key take-home: Germline TRAF7 missense variants should be considered in patients with developmental delay accompanied by cardiac, facial, and digital anomalies, enabling precise genetic diagnosis and management.

References

• American journal of human genetics • 2018 • De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features. PMID:29961569
• Genetics in medicine • 2020 • Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. PMID:32376980
• Frontiers in medicine • 2021 • Case Report: Blepharophimosis and Ptosis as Leading Dysmorphic Features of Rare Congenital Malformation Syndrome With Developmental Delay - New Cases With TRAF7 Variants. PMID:34513876
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. PMID:37043537

Evidence Based Scoring (AI generated)