De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

Abstract

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

A machine learning approach to predicting autism risk genes: Validation of known genes and discovery of new candidates

“…Our ranking system also successfully predicted another ASD gene FBXO11 (ranked sixth). FBXO11 was prioritized as a strong ASD candidate gene (43), and was recently reported to be associated with a variable neurodevelopmental disorder (44). Additionally, mutations in another two genes, NBEA1 and ATRX, ranked fourth and fifth in our analysis, have also been identified with ASD according to SFARI Gene resource.…”

From man to fly – convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes

“…Further F‐box genes have been found associated with neurodevelopmental disorders, too, as for example, reported in a patient with intellectual disability and seizures carrying a deletion of FBXO28 (Au et al, ). Another study reports de novo variants in FBXO11 in 20 patients, of which 17 show behavioral problems, such as autistic‐like features and ADHD‐related traits (Gregor et al, ). TDRP , the second gene in the microduplication, is known to be involved in sperm motility (Mao et al, ).…”

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.…”