Limb disorders
Gene: FBXW11
FBXW11 has been copied to this panel from the Intellectual disability - microarray and sequencing panel, on the recommendation of Helen Brittain (Genomics England, Clinical Fellow). In addition to intellectual disability and neurodevelopmental delay, table 1 in PMID: 31402090 outlines other features that are associated with FBXW11 variants. These include mandibular abnormalities (5/7 cases), abnormalities in hands and feet (4/7 cases) and skeletal changes (2/7 cases).Created: 4 Jan 2024, 1:02 p.m. | Last Modified: 4 Jan 2024, 1:02 p.m.
Panel Version: 4.34
The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.Created: 4 May 2024, 3:32 p.m. | Last Modified: 6 May 2024, 9:28 p.m.
Panel Version: 5.4
Comment on phenotypes: Added disease association which has been added in OMIM.Created: 15 Jul 2020, 2:13 p.m. | Last Modified: 15 Jul 2020, 2:13 p.m.
Panel Version: 3.172
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
FBXW11 has been identified by Konstantinos Varvagiannis following a publication from Holt et al. (2019 - PMID: 31402090). 7 individuals with a missense de novo variants. Trio WES performed in 5/7 individuals. Sufficient number of individuals identified with ID/DD (6/7). Also similar phenotype seen in Koolen et al, 2006 - PMID: 16865294, where a 7 gene microduplication involving FBXW11.
Functional work on both embryo and zebra fish to support the phenotype and FBXW11 is associated with a phenotype in Gene2Phenotype.
Therefore rating FBXW11 as Green.Created: 7 Oct 2019, 1:41 p.m. | Last Modified: 7 Oct 2019, 1:41 p.m.
Panel Version: 2.1064
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Holt et al. (2019 - PMID: 31402090) report on 7 unrelated individuals with de novo FBXW11 variants.
Features included DD (6/7), ID (6/7 - severity relevant to the current panel in most cases), eye, digital, jaw anomalies, etc. There was some overlap with the phenotype of a 1.24-Mb 5q35.1 microduplication spanning FBXW11 and 6 additional genes (Koolen et al, 2006 - PMID: 16865294).
FBXW11 encodes an F-box protein part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degratation. The SCF complex functions as a regulator of Wnt/β-catenin, Hh (and possibly RAS) signalling pathways.
Each individual harbored a private missense variant as a de novo event. Alternative diagnoses (eg. Noonan syndrome in the case of a suggestive phenotype) were ruled out to the extent possible.
All 7 variants localized in regions depleted for nonsynonymous variation (constrained coding regions) at the tips of loops of the WD repeat domains and were presumed to lead to destabilization of the protein and/or its interactions. Given the clustering a gain-of-function or dominant-negative effect of these variants might be suggested. [In gnomAD FBXW11 has a Z score = 3.96 for missense variants / pLI = 0.98].
In situ hybridization on human embryo sections demonstrated expression in the developping eye, hand, brain and mandibular process.
Relevant expression patterns were also observed for the 2 zebrafish orthologs of FBXW11, fbxw11a/b. Generated zebrafish homozygous for a frameshift fbxw11b frameshift variant demonstrated relevant phenotypes upon additional injection of a fbxw11a morpholino (abnormal pectoral fins, heart edema, smaller eyes, abnormal jaw development).
FBXW11 is not associated with any phenotype in OMIM/G2P.
As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, expression, phenotype in zebrafish model, etc.) or amber.
Sources: LiteratureCreated: 25 Aug 2019, 8:01 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit
Publications
Tag Q4_21_NHS_review was removed from gene: FBXW11. Tag Q4_23_promote_green was removed from gene: FBXW11.
Source NHS GMS was added to FBXW11. Source Expert Review Green was added to FBXW11. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
gene: FBXW11 was added gene: FBXW11 was added to Limb disorders. Sources: Literature,Expert Review Amber Q4_21_NHS_review, Q4_23_promote_green tags were added to gene: FBXW11. Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBXW11 were set to 31402090 Phenotypes for gene: FBXW11 were set to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:0030057 Penetrance for gene: FBXW11 were set to unknown