TRAF7 is a known mediator of the MAPK and NFKB signaling pathways and is involved in multiple biologic processes, such as ubiquitination. TRAF7 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2018 (Tokita et al., PMID: 29961569). This is a multisystemic developmental disorder with developmental delay/intellectual disability, variable cardiac and digital anomalies, and recognizable facial features. Some patients may have autism spectrum disorder, seizures, hearing loss or ocular abnormalities. Thirteen de novo missense variants that have been reported in 16 probands in 2 publications (PMIDs: 29961569, 32376980) are included in this curation. More genetic evidence is available in the literature (PMIDs: 34513876, 37067385, 38569228, 38612512) but the maximum score for genetic evidence (12 points) has been reached. Several variants are recurrent (including p.Arg655Gln and p.Phe617Leu), and most cluster within the WD40 repeats of the TRAF7 protein, suggesting dominant-negative and/or gain-of-function effects.
This gene-disease relationship is also supported by zebrafish and xenopus traf7 model systems (PMID: 37043537), and functional studies demonstrating transcriptional changes and altered ERK signaling in the presence of pathogenic TRAF7 variants (PMID: 29961569, 32376980).
In summary, there is definitive evidence supporting the relationship between TRAF7 and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panels on the meeting date September 6, 2023 (SOP Version 9).
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