Intellectual disability - microarray and sequencing
Gene: FBXO11 Green List (high evidence)Comment on list classification: Appropriate phenotype, sufficient number of cases.Created: 5 Oct 2018, 8:38 a.m.
Comment when marking as ready: Appropriate phenotype and sufficient casesCreated: 5 Oct 2018, 8:19 a.m.
Green List (high evidence)
PMID 30057029 is a collaborative study (including individuals from the DDD study) on 20 individuals with de novo FBXO11 variants including 8 missense variants, 10 likely gene desrupting (or LGD incl. nonsense, splice site, frameshift), 1 partial gene deletion and 1 whole gene deletion. Developmental delay was universal feature and most individuals presented with ID (profound in those with missense, severe in those with LGD variants, 2 individuals with normal IQ but difficulties in specific domains). 85% presented with behavioral anomalies incl.autistic features. 5 individuals (25%) were reported to have seizures. Cleft lip/palate/bifid uvula was a feature in 3 subjects (15%). Variable occipitofrontal circumference and skeletal features. The authors suggest loss-of-function/haploisufficiency as a plausible mechanism although gain-of-function and dominant negative effects were possible, particularly for missense variants. //
PMID 29796876 reports on 2 individuals, one with de novo insertion affecting a splice donor site, the other with a de novo frameshift variant, both with developmental delay, intellectual disability and behavioral problems. Microcephaly and cleft lip/alveolus were features in one individual. Seizures were not noted. //
De novo variants in individuals with intellectual disability had previously been reported without clinical details in PMID 27620904 (1 individual with the same frameshift variant as in PMID 29796876) as well as in a meta-analysis of 2104 trios with intellectual disability (PMID 27479843 - 2 individuals). //
As pointed out in 30057029, a study of 152 consanguineous families with neurodevelopmental disorders (PMID 28097321) had previously identified one individual homozygous for a missense FBXO11 variant (individual MR136). This subject was reported to have hypotonia, severe intellectual disability and EEG abnormalities.
As a result other modes of inheritance (eg. BOTH monoallelic and biallelic, with biallelic causing a more severe phenotype) cannot be ruled out - and may be considered.Created: 15 Aug 2018, 7:32 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Publications
Gene: fbxo11 has been classified as Green List (High Evidence).
Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Phenotypes for gene: FBXO11 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
FBXO11 was added to Intellectual disability panel. Sources: Literature
FBXO11 was created by Konstantinos Varvagiannis
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.