De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

Abstract

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

Fig. 1

FBXO11 with deletions and variants identified in our cohort. FBXO11 is expressed in two different isoforms (NM_001190274.1 and NM_0251433.4), which differ by an alternative exon 1, and of which NM_001190274.1 represents the longest transcript. Variants are annotated based on NM_0011190274.1. FBXO11 protein domains are depicted in color. Individuals 6 and 7 have a partial deletion of FBXO11 (gray bars)

Fig. 2

Photographs of individuals with a variant in FBXO11. The first row shows the individuals at a younger age, and the second row shows the respective individual at an older age. Facial features comprise a broad forehead, long palpebral fissures, and a thin upper lip with a broad space between the paramedian peaks of the upper lip. Some individuals show coarsening at an older age. The third row shows the hands of the respective individual with brachydactyly and tapering fingers in several cases

Fig. 3

a Detailed photographs of the eyes of individuals with a variant in FBXO11. Eyes show long palpebral fissures. b Detailed photographs of the lips of individuals with a variant in FBXO11. There is a thin upper lip with a broad space between the paramedian peaks of the upper lip