Intellectual disability - microarray and sequencing
Gene: FBXW11 Green List (high evidence)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
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
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: 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
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
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
Gene: fbxw11 has been classified as Green List (High Evidence).
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.