De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms - Sorbonne Université Access content directly
Journal Articles European Journal of Human Genetics Year : 2019

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

Anthonie van Essen
  • Function : Author
Charu Kaiwar
Marije Meuwissen
  • Function : Author
Kristin Monaghan
  • Function : Author
Hilary Racher
  • Function : Author

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.

Dates and versions

hal-04555858 , version 1 (23-04-2024)

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Sandra Jansen, Ilse van der Werf, a Micheil Innes, Alexandra Afenjar, Pankaj Agrawal, et al.. De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms. European Journal of Human Genetics, 2019, 27 (5), pp.738-746. ⟨10.1038/s41431-018-0292-2⟩. ⟨hal-04555858⟩
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