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

Sandra Jansen, Ilse M. van der Werf, A. Micheil Innes, Alexandra Afenjar, Pankaj B. Agrawal, Ilse J. Anderson, Paldeep S. Atwal, Ellen van Binsbergen, Marie José van den Boogaard, Lucia Castiglia, Zeynep H. Coban-Akdemir, Anke van Dijck, Diane Doummar, Albertien M. van Eerde, Anthonie J. van Essen, Koen L. van Gassen, Maria J. Guillen Sacoto, Mieke M. van Haelst, Ivan Iossifov, Jessica L. JacksonElizabeth Judd, Charu Kaiwar, Boris Keren, Eric W. Klee, Jolien S. Klein Wassink-Ruiter, Marije E. Meuwissen, Kristin G. Monaghan, Sonja A. de Munnik, Caroline Nava, Charlotte W. Ockeloen, Rosa Pettinato, Hilary Racher, Tuula Rinne, Corrado Romano, Victoria R. Sanders, Rhonda E. Schnur, Eric J. Smeets, Alexander P.A. Stegmann, Asbjørg Stray-Pedersen, David A. Sweetser, Paulien A. Terhal, Kristian Tveten, Grace E. VanNoy, Petra F. de Vries, Jessica L. Waxler, Marcia Willing, Rolph Pfundt, Joris A. Veltman, R. Frank Kooy, Lisenka E.L.M. Vissers, Bert B.A. de Vries

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)738-746
Number of pages9
JournalEuropean Journal of Human Genetics
Volume27
Issue number5
DOIs
StatePublished - May 1 2019

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    Jansen, S., van der Werf, I. M., Innes, A. M., Afenjar, A., Agrawal, P. B., Anderson, I. J., Atwal, P. S., van Binsbergen, E., van den Boogaard, M. J., Castiglia, L., Coban-Akdemir, Z. H., van Dijck, A., Doummar, D., van Eerde, A. M., van Essen, A. J., van Gassen, K. L., Guillen Sacoto, M. J., van Haelst, M. M., Iossifov, I., ... de Vries, B. B. A. (2019). De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms. European Journal of Human Genetics, 27(5), 738-746. https://doi.org/10.1038/s41431-018-0292-2