The gene
FBXO28 encodes an F-box protein — one component of a larger cellular machine called an SCF ubiquitin ligase. The job of that machine is to tag other proteins for disposal. Cells depend on this constant, precise clearing-out: proteins that are damaged, or that have finished the job they were made for, have to be removed on schedule. When the tagging goes wrong, the wrong proteins persist, or the right ones disappear too early.
FBXO28 has been studied for over a decade, mostly by cancer researchers. In 2013 a group at the Karolinska Institutet showed that FBXO28 acts on MYC, one of the most intensively studied cancer genes, and that its activity predicts outcome in breast cancer (Cepeda et al., EMBO Molecular Medicine, PMID 23776131). Later work showed the protein is required for normal progression through cell division (Kratz et al., Cell Cycle, 2016, PMID 27754753) and that it regulates its own destruction (Cai et al., Cell Signalling, 2020, PMID 31678254).
The disorder
Developmental and Epileptic Encephalopathy 100 — DEE100, catalogued as OMIM #619777 — is caused by disease-causing variants in FBXO28. The link was first suspected in 2014, when a Canadian group narrowed the critical region of the 1q41q42 microdeletion syndrome and named FBXO28 as the candidate gene for intellectual disability and seizures (Au et al., PMID 24357076). It was confirmed in 2018 with the first point mutation described independently of a deletion (Balak et al., PMID 30160831), and defined as a clinical entity across an international patient series in 2021 (Schneider et al., Epilepsia, PMID 33280099).
Fewer than twenty people have been reported worldwide.
What it looks like
Reported features include developmental delay, intellectual disability, low muscle tone, epilepsy including infantile spasms, feeding difficulties, movement disorders, and visual impairment including cortical visual impairment. A hyperkinetic movement disorder has been described (Krygier et al., Seizure, 2024, PMID 38728953). Paroxysmal upward eye deviation has been reported and can be mistaken for a seizure.
Not every child has every feature, and the range of severity is not yet well understood — which is precisely why a natural history study matters.
What is not known
There is no disease-modifying therapy. More fundamentally, nobody yet knows what a disease-causing FBXO28 variant does to the protein in a living cell. In the patients studied by this Foundation, the fault sits in the last part of the gene, so the cell most likely still produces the protein, only shortened. Whether that shortened protein is simply inactive, actively harmful, or ends up in the wrong place inside the cell is an open question — and each answer points to a different kind of therapy.
Settling that question is the Foundation’s first objective.
Medical disclaimer: this page is provided for educational purposes and does not replace consultation with a qualified healthcare professional. Clinical statements are attributed to the cited literature.
If FBXO28 appears in your family’s genetic report
We would like to hear from you. Fewer than twenty people have been reported worldwide, so every family we learn of changes what is possible — for the science and for the children. Clinicians and researchers are equally welcome to get in touch.