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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.

Original publication

DOI

10.1016/j.ajhg.2018.07.003

Type

Journal article

Journal

Am J Hum Genet

Publication Date

02/08/2018

Volume

103

Pages

305 - 316

Keywords

FBXO11, intellectual disability, neurodevelopmental disorder, Child, Exome, F-Box Proteins, Female, Genetic Association Studies, Genetic Variation, Humans, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Proteasome Endopeptidase Complex, Protein-Arginine N-Methyltransferases, Ubiquitin-Protein Ligases, Ubiquitination, Whole Exome Sequencing