FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

Abstract

Chromosome 1q41‐q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41‐q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41‐q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41‐q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41‐q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug‐resistant epilepsy, and hyperkinetic movement disorders.

Data-driven historical characterization of epilepsy-associated genes

“…The majority of Tier 1 epilepsy genes (126/143) were also found in at least one of the four assessed gene panels. Those 17 high-confidence genes not included in the assessed panels include genes both gene associated with somatic variants (e.g., BRAF [24]) and genes that should be added to gene panels (e.g., FBXO28 [25] or KCNC2 [26]). When comparing our comprehensive Tier 2 gene list of 738 genes with (caption on next page) the gene panel genes, we found that almost 50% of those genes (n = 365) are included in at least one of the gene panels.…”

High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders

“…All three patients with variants in WDR26/FBXO28 were affected by severe ID, epilepsy, dysmorphia, behavioral abnormalities, and central nervous system alterations, including incomplete hippocampal inversion, corpus callosum hypoplasia, or cerebellar atrophy. None of our patients showed the characteristic multi-system features of patients affected by 1q41-q42 deletion syndrome [ 39 ].…”

FBXO28 promotes cell proliferation, migration and invasion via upregulation of the TGF-beta1/SMAD2/3 signaling pathway in ovarian cancer

“…In recent years, evidence has implied that FBXO28 may be involved in the occurrence and development of multiple human diseases. For example, FBXO28 variants cause developmental and epileptic encephalopathy, and with severe intellectual disability [ 31 ]. It has been found that FBXO28 is needed for the normal mitosis and affects the cell cycle by regulating topoisomerase IIα activity to maintain genome stability [ 32 ].…”