Submission Details

Autosomal dominant

01/24/2020

The FBXW11 gene is located on chromosome 5 at 5q35.1 and encodes the F-box and WD repeat domain containing 11 protein. This F-box protein functions as part of a ubiquitin ligase complex and is involved in ubiquitin-mediated protein degradation. FBSW11 also participates in the Wnt/β-catenin and Hh signalling pathways, which play critical roles in early embryonic development and tissue patterning. FBXW11 was first reported in relation to autosomal dominant FBXW11-related neurodevelopmental, brain, jaw, eye and digital anomalies in 2019 (31402090: Holt et al. 2019). Evidence supporting this gene-disease relationship includes case-level data and expereimental data. Seven unique heterozygous missense variants in this gene have been reported in seven individuals in a single cross-institutional publication (31402090: Holt et al. 2019). All variants occurred de novo. The maximum score for genetic evidence (12 pts) has been reached. Structural analyses indicated the variants clustered at the surface of the substrate-binding domain of FBXW11 and were predicted to destabilize the protein and/or its interactions, but the mechansim of disease has not yet been definitively determined. This gene-disease relationship is also supported by the gene's role in the Hh and Wnt/β-catenin signalling pathways, in which multiple genes have been linked to similar clinical phenotypes, tissue expression in the clinically affected systems in both humans and zebrafish, and a zebrafish knockdown model that shows eye, jaw, and pectoral fin anomalies that correlate with the phenotypes observed in humans (31402090: Holt et al. 2019). In summary, there is strong evidence to support the relationship between FBXW11 and autosomal dominant neurodevelopmental, brain, eye, and digit anomalies. Additional reports in humans published three years from the first proposal of the association are needed to reach a definitive classification.

31402090