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Genetic epilepsy syndromes

Gene: FBXO11

Green List (high evidence)

FBXO11 (F-box protein 11)
EnsemblGeneIds (GRCh38): ENSG00000138081
EnsemblGeneIds (GRCh37): ENSG00000138081
OMIM: 607871, Gene2Phenotype
FBXO11 is in 7 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

AD intellectual developmental disorder with dysmorphic facies and behavioural abnormalities (IDDFBA) - syndromic intellectual disorder. Gregor et al, 2018 - 18 unrelated patients all had delayed psychomotor development and ID ranged from nild-mod.Only 5/20 patients had seizures and the severity ranged from epileptic encephalopathy to 1 seizure. de novo het variants detected in all 18 (10 nonsense, splice site or fs and 8 missense) two additional partients carried larger deletions, 1 of which had deletions of additional genes. Functional studies not done. Fritzen et al, 2028 - 2 unrelated boys - neither mentioned as having seizures/epilepsy - de novo het variants, no functional work done. therefore ~25% of cases - epilepsy is a feature.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, 618089

Publications

Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for FBXO11 related intellectual disability. Seizures reported in at least 5 unrelated cases carrying de novo monoallelic FBXO11 variants (PMID: 30057029).
Created: 25 Sep 2018, 3:38 p.m.
Comment on phenotypes: Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Created: 25 Sep 2018, 2:10 p.m.

Konstantinos Varvagiannis (Other)

I don't know

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 in any of these individuals. //

The following studies provide further evidence for a FBXO11-related neurodevelopmental phenotype although, possibly NOT relevant for the phenotype of epilepsy :

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, 7:39 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
OMIM
607871
Clinvar variants
Variants in FBXO11
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to FBXO11.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to FBXO11.

11 Dec 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Konstantinos Varvagiannis: PMID 30057029 is a collaborati

25 Sep 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: fbxo11 has been classified as Green List (High Evidence).

25 Sep 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: fbxo11 has been classified as Green List (High Evidence).

25 Sep 2018, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: FBXO11 were set to 30057029

25 Sep 2018, Gel status: 0

Set Phenotypes

Sarah Leigh (Genomics England Curator)

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

15 Aug 2018, Gel status: 0

Added New Source

Konstantinos Varvagiannis (Other)

FBXO11 was added to Genetic Epilepsy Syndromes panel. Sources: Literature

15 Aug 2018, Gel status: 0

Created

Konstantinos Varvagiannis (Other)

FBXO11 was created by Konstantinos Varvagiannis