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Intellectual disability

Gene: FBXO28

Green List (high evidence)
FBXO28 (F-box protein 28)
EnsemblGeneIds (GRCh38): ENSG00000143756
EnsemblGeneIds (GRCh37): ENSG00000143756
OMIM: 609100, Gene2Phenotype
FBXO28 is in 3 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

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: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).
Created: 25 Aug 2022, 4:34 p.m. | Last Modified: 25 Aug 2022, 4:34 p.m.
Panel Version: 3.1695
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 25 Aug 2022, 4:26 p.m. | Last Modified: 25 Aug 2022, 4:26 p.m.
Panel Version: 3.1695
Created: 25 Aug 2022, 4:26 p.m.
Last Modified: 25 Aug 2022, 4:26 p.m.
Panel version: 3.1695

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous pathogenic FBXO28 variants cause Developmental and epileptic encephalopathy 100 (# 619777).

At least 10 individuals with monoallelic missense / truncating FBXO28 variants have been reported. The subject with de novo frameshift variant initially reported by Balak et al (2018 - PMID:30160831) was included with additional clinical details in a recent report along with 9 further individuals (Schneider et al, 2021 - PMID: 33280099).

The phenotype corresponds to a developmental and epileptic encephalopathy with severe/profound ID. As discussed by Schneider et al, all individuals had DD prior to seizure onset which occurred at a median age of 22.5 months (range: 8m - 5y). The authors noted that missense variants may be associated with a milder phenotype (e.g. seizures occurred at the age of 4-5 years in 3 individuals).

Given these, FBXO28 appears to be relevant for inclusion in the current panel, with investigations prior to seizure onset.

As in the summary by Schneider et al, the gene encodes F-box only protein 28, a ubiquitin ligase promoting ubiquitination and degradation of phosphorylated proteins.

While FBXO28 has been suggested to have a critical role in 1q41q42 deletions (most spanning also WDR26) the authors note that a mechanism different than haploinsufficiency may underly FBXO28 encephalopathy.

Importantly, all 5 truncating variants reported (and 2/4 missense ones) occurred in the last exon, making these variants less susceptible to NMD. 2 other (of the 4) missense variants clustered in the F-box domain, which the authors hypothesize may correspond to a second pathogenic region.

7/9 variants arose de novo while 2 individuals had inherited a missense and a stopgain variant from mosaic unaffected parents (2.5% and 6%).

A comparison of the FBXO28-associated phenotype with the respective of 1q41q42 deletions and WDR26-related NDD is also made.

Consider inclusion in the ID panel with green (or amber) rating. Please consider inclusion in other possibly relevant panels (e.g. microcephaly (4/10), movement disorders, etc).
Sources: Literature
Created: 25 Apr 2022, 12:57 p.m.

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

Phenotypes
Developmental and epileptic encephalopathy 100 (# 619777)

Publications

Created: 25 Apr 2022, 12:57 p.m.

Panel version: 3.1561

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Developmental and epileptic encephalopathy 100, OMIM:619777
  • developmental and epileptic encephalopathy 100, MONDO:0030695
OMIM
609100
Clinvar variants
Variants in FBXO28
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: FBXO28. Tag Q3_22_MOI was removed from gene: FBXO28.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to FBXO28. Source Expert Review Green was added to FBXO28. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

25 Aug 2022, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy 100 (# 619777) to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695

25 Aug 2022, Gel status: 2

Added Tag, Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: FBXO28. Tag Q3_22_MOI tag was added to gene: FBXO28.

25 Aug 2022, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: fbxo28 has been classified as Amber List (Moderate Evidence).

25 Apr 2022, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: FBXO28 was added gene: FBXO28 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBXO28 were set to 30160831; 33280099 Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy 100 (# 619777) Penetrance for gene: FBXO28 were set to unknown Review for gene: FBXO28 was set to GREEN