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 nextgeneration 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.

Epigenome-wide association study of seizures in childhood and adolescence

“…Single nucleotide polymorphisms within MACROD2 have previously been associated with autism, although with rather weak evidence [53], and other brain-related traits such as intelligence and mathematical abilities [54]. Individuals with de novo mutations in FBXO11, an analogous of PRMT10, have been reported to show intellectual disability and autism [55]. Although both genes are predominantly expressed in non-neural tissues, these studies suggest that MACROD2 and PRMT10 could play a role in brain functioning, and their methylation status could plausibly be involved in seizures.…”

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies

“…Recently, WES and WGS and the international collation of affected individuals with variants in the same gene 1 , 2 have led to the identification of several developmental disorders. This approach, referred to as “reverse phenotyping,” has been successfully applied to multiple intellectual disability syndromes, including those related to genetic variants in FBXO11 (MIM: 607871 ), 3 , 4 , 5 and syndromes involving variants in CDC42 (MIM: 116952 ) and RAC1 (MIM: 602048 ), 6 , 7 all of which display clinical heterogeneity. Here, we use a similar approach to investigate the role of de novo variants in FBXW11 (MIM: 605651 ) in human development.…”

“…From the published images, it also appears that he has broad halluces and short terminal phalanges. The latter are interesting because individual 4 had bilateral shortening of the thumbs and big toes, individuals 2, 4, and 7 had short terminal phalanges and/or brachydactyly, and individuals 2 and 4 had underdevelopment of the thenar eminence, akin to “finger-like thumbs.” Although overlapping features can be seen, there is phenotypic diversity, which appears to be an emerging pattern for variants affecting genes controlling multiple cellular pathways and developmental processes; these gene include, for example, CDC42 , 6 FBXO11 , 3 , 4 , 5 SHH (MIM: 600725 ), 15 , 16 and SOX2 (MIM: 184429 ). 17 , 18 …”

“… 19 WD40-repeats are also a motif of approximately 40 amino acids and typically fold into a β-propeller structure that is involved in protein-protein interaction. 20 , 21 Alterations in other F-box genes, for example FBXO11 3 , 4 , 5 and FBXL4 (MIM: 605654 ), have been associated with neurodevelopmental disorders. 22 FBXW11 is a substrate adaptor of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, which catalyzes phosphorylation-dependent ubiquitination.…”

What’s in a name? Issues to consider when naming Mendelian disorders

“…Gene names are established through the HUGO Gene Nomenclature Committee, 5 which assigns unique symbols and names to human genes, based on function, sequence similarity, homology in another species, clone designation, or chromosome location. Some of the newly identified phenotypes have been recognized using “reverse phenotyping,” 6 in which a pathogenic gene variant is identified in a group of patients first, followed by identification and description of the associated phenotype: identification of a gene before describing the phenotype might make naming phenotypes after genes appear to be a logical approach. Some examples of the approach of giving phenotypes names of causative genes include DICER1 syndrome, 7 a condition that increases the risk of certain malignant and benign tumors (MIM 138800, MIM 601200, and MIM 180295), caused by pathogenic variants in the DICER1 gene (MIM 606241); FOXG1 syndrome, 8 a congenital variant of Rett syndrome (MIM 613454), caused by pathogenic variants in the FOXG1 gene (MIM 164874); and MYH9-related disorders, 9 characterized by macrothrombocytopenia and granulocyte inclusions, with or without nephritis or sensorineural hearing loss (MIM 155100), caused by pathogenic variants in the MYH9 gene (MIM 160775).…”