A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype

Abstract

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome.

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

“…Intellectual disability was classified as profound in patients who were nonverbal, nonambulatory, and fully dependent and severe in patients who could walk or communicate with nonverbal signs or follow simple commands. Our phenotypic analysis incorporated additional information on the published patient (Patient 3) 4 . International League Against Epilepsy (ILAE) classification criteria was used to categorize seizure types and epilepsy syndromes 6 …”

“…Chromosome 1q41‐q42 deletion syndrome (OMIM 612530) includes developmental delay, seizures, and dysmorphic features 1–3 . Two of the six genes in the common microdeletion, WDR26 and FBXO28 , have been implicated in causing monogenic disease 4,5 . There is significant overlap in the clinical features of patients with pathogenic sequence variants in WDR26 and those of patients with 1q41‐q42 deletion syndrome; therefore, WDR26 has been postulated as the main genetic driver of the 1q41‐q42 deletion phenotype 5 .…”

“…There is significant overlap in the clinical features of patients with pathogenic sequence variants in WDR26 and those of patients with 1q41‐q42 deletion syndrome; therefore, WDR26 has been postulated as the main genetic driver of the 1q41‐q42 deletion phenotype 5 . Only one patient with a de novo FBXO28 pathogenic variant has been described with profound intellectual disability, intractable epilepsy, and dysmorphic features 4 . When considering patients with de novo 1q41‐q42 deletions, Balak and colleagues found that 30 of 37 patients had deletions spanning FBXO28 4 .…”

“…Only one patient with a de novo FBXO28 pathogenic variant has been described with profound intellectual disability, intractable epilepsy, and dysmorphic features 4 . When considering patients with de novo 1q41‐q42 deletions, Balak and colleagues found that 30 of 37 patients had deletions spanning FBXO28 4 . Of the patients older than 2 years, 76% (16/21) had seizures, compared to 25% of patients with deletions that did not encompass FBXO28 4 .…”

“…When considering patients with de novo 1q41‐q42 deletions, Balak and colleagues found that 30 of 37 patients had deletions spanning FBXO28 4 . Of the patients older than 2 years, 76% (16/21) had seizures, compared to 25% of patients with deletions that did not encompass FBXO28 4 . Thus FBXO28 may be an important contributor to the 1q41‐q42 deletion syndrome phenotype.…”