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.
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We thank the individuals and their parents for participating in the study. We also thank Megan Cho, from GeneDx, Gaithersburg, MD, USA, for her help in contacting referring clinicians. We would like to thank Marisa Andrews and Dustin Baldridge, from the Department of Pediatrics, Washington University School of Medicine, and John N. Constantino, from the Department of Psychiatry and Pediatrics, Washington University School of Medicine, for their clinical support. We would also like to thank Christian Gilissen, from the Department of Human Genetics, Nijmegen, The Netherlands, for his support in comparing the frequency of de novo variants in FBXO11 to the gene-specific mutation rate. This work was financially supported by grants from the Netherlands Organization for Health Research and Development (912-12-109 to JAV, LELMV, and BBAdV). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH under award number U54HD087011, the Intellectual and Developmental Disabilities Research Center at Washington University. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data are available from http://decipher.sanger.ac.uk and via email from firstname.lastname@example.org. Funding for the project was provided by the Wellcome Trust. We would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.
Conflict of interest
M.J.G.S., K.G.M., and R.E.S. are employees of GeneDx Inc. H.R. is an employee of Impact Genetics Inc. The other authors declare that they have no conflict of interest.
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Annals of Human Genetics (2019)
De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies
The American Journal of Human Genetics (2019)