학술논문
De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms
Document Type
Original Paper
Author
Jansen, Sandra; van der Werf, Ilse M.; Innes, A. Micheil; Afenjar, Alexandra; Agrawal, Pankaj B.; Anderson, Ilse J.; Atwal, Paldeep S.; van Binsbergen, Ellen; van den Boogaard, Marie-José; Castiglia, Lucia; Coban-Akdemir, Zeynep H.; van Dijck, Anke; Doummar, Diane; van Eerde, Albertien M.; van Essen, Anthonie J.; van Gassen, Koen L.; Guillen Sacoto, Maria J.; van Haelst, Mieke M.; Iossifov, Ivan; Jackson, Jessica L.; Judd, Elizabeth; Kaiwar, Charu; Keren, Boris; Klee, Eric W.; Klein Wassink-Ruiter, Jolien S.; Meuwissen, Marije E.; Monaghan, Kristin G.; de Munnik, Sonja A.; Nava, Caroline; Ockeloen, Charlotte W.; Pettinato, Rosa; Racher, Hilary; Rinne, Tuula; Romano, Corrado; Sanders, Victoria R.; Schnur, Rhonda E.; Smeets, Eric J.; Stegmann, Alexander P. A.; Stray-Pedersen, Asbjørg; Sweetser, David A.; Terhal, Paulien A.; Tveten, Kristian; VanNoy, Grace E.; de Vries, Petra F.; Waxler, Jessica L.; Willing, Marcia; Pfundt, Rolph; Veltman, Joris A.; Kooy, R. Frank; Vissers, Lisenka E. L. M.; de Vries, Bert B. A.
Source
European Journal of Human Genetics. 27(5):738-746
Subject
Language
English
ISSN
1018-4813
1476-5438
1476-5438
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.