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Intellectual disability

Gene: FBXW11

Green List (high evidence)
FBXW11 (F-box and WD repeat domain containing 11)
EnsemblGeneIds (GRCh38): ENSG00000072803
EnsemblGeneIds (GRCh37): ENSG00000072803
OMIM: 605651, Gene2Phenotype
FBXW11 is in 5 panels

3 reviews

Eleanor Williams (Genomics England Curator)

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
Created: 15 Jul 2020, 2:13 p.m.
Last Modified: 15 Jul 2020, 2:13 p.m.
Panel version: 3.172

Catherine Snow (Genomics England)

Green List (high evidence)

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

Created: 7 Oct 2019, 1:41 p.m.
Last Modified: 7 Oct 2019, 1:41 p.m.
Panel version: 2.1064

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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: Literature
Created: 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

Created: 25 Aug 2019, 8:01 p.m.

Panel version: 2.1015

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914
  • neurodevelopmental, jaw, eye, and digital syndrome, MONDO:003005
OMIM
605651
Clinvar variants
Variants in FBXW11
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

4 Jan 2024, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914 to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:003005

15 Jul 2020, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914

7 Oct 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: fbxw11 has been classified as Green List (High Evidence).

25 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: FBXW11 was added gene: FBXW11 was added to Intellectual disability. Sources: Literature 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 Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit Penetrance for gene: FBXW11 were set to unknown Review for gene: FBXW11 was set to GREEN