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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Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet (Lond, Engl). 2012;380:1674–82.
Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7.
Wright CF, Fitzgerald TW, Jones WD, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet (Lond, Engl). 2015;385:1305–14.
Grozeva D, Carss K, Spasic-Boskovic O, et al. Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutat. 2015;36:1197–204.
Iossifov I, O'Roak BJ, Sanders SJ, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21.
Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18.
Thevenon J, Duffourd Y, Masurel-Paulet A, et al. Diagnostic odyssey in severe neurodevelopmental disorders: towards clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet. 2016;89:700–7.
de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–9.
Seaby EG, Pengelly RJ, Ennis S. Exome sequencing explained: a practical guide to its clinical application. Brief Funct Genomics. 2016;15:374–84.
Vulto-van Silfhout AT, Gilissen C, Goeman JJ, et al. Quantification of Phenotype Information Aids the Identification of Novel Disease Genes. Hum Mutat. 2017;38:594–9.
Ba W, Yan Y, Reijnders MR, et al. TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function. Hum Mol Genet. 2016;25:892–902.
Schulze TG, McMahon FJ. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum Hered. 2004;58:131–8.
de Goede C, Yue WW, Yan G, et al. Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders. Eur J Paediatr Neurol. 2016;20:286–95.
Nambot S, Masurel A, El Chehadeh S, et al. 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping. Eur J Hum Genet. 2016;24:830–7.
Au PY, You J, Caluseriu O, et al. GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK. Hum Mutat. 2015;36:1009–14.
Silverman JS, Skaar JR, Pagano M. SCF ubiquitin ligases in the maintenance of genome stability. Trends Biochem Sci. 2012;37:66–73.
Yang Y, Hadjikyriacou A, Xia Z, et al. PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. Nat Commun. 2015;6:6428.
Le Poole IC, Sarangarajan R, Zhao Y, et al. “VIT1”, a novel gene associated with vitiligo. Pigment cell research/sponsored by the European Society for Pigment Cell Research and the International Pigment Cell. Society. 2001;14:475–84.
Duan S, Cermak L, Pagan JK, et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature. 2012;481:90–3.
Martinez F, Caro-Llopis A, Rosello M, et al. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2017;54:87–92.
Lelieveld SH, Reijnders MR, Pfundt R, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19:1194–6.
O'Roak BJ, Vives L, Fu W, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science (New York, NY). 2012;338:1619–22.
Coe BP, Witherspoon K, Rosenfeld JA, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014;46:1063–71.
Sobreira N, Schiettecatte F, Boehm C, et al. New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene. Hum Mutat. 2015;36:425–31.
Sobreira N, Schiettecatte F, Valle D, et al. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–30.
Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524–33.
Samocha KE, Robinson EB, Sanders SJ, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46:944–50.
Tasaki T, Mulder LC, Iwamatsu A, et al. A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Mol Cell Biol. 2005;25:7120–36.
Kipreos ET, Pagano M. The F-box protein family. Genome Biol. 2000;1:3002. Reviews.
Nelson DE, Randle SJ, Laman H. Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins. Open Biol. 2013;3:130131.
Borg NA, Dixit VM. Ubiquitin in cell-cycle regulation and dysregulation in cancer. Annu Rev Cancer Biol. 2017;1:59–77.
Zheng N, Zhou Q, Wang Z, et al. Recent advances in SCF ubiquitin ligase complex: clinical implications. Biochim Biophys Acta. 2016;1866:12–22.
Tarpey PS, Raymond FL, O'Meara S, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet. 2007;80:345–52.
Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15:70–3.
Bhutani S, Das A, Maheshwari M, et al. Dysregulation of core components of SCF complex in poly-glutamine disorders. Cell Death Dis. 2012;3:e428.
Di Fonzo A, Dekker MC, Montagna P, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology. 2009;72:240–5.
Mir A, Sritharan K, Mittal K, et al. Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family. Hum Genet. 2014;133:975–84.
Au PY, Argiropoulos B, Parboosingh JS, et al. Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures. Am J Med Genet A. 2014;164a:441–8.
Jin Y, Shenoy AK, Doernberg S, et al. FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. Cancer Lett. 2015;362:70–82.
Hardisty-Hughes RE, Tateossian H, Morse SA, et al. A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse. Hum Mol Genet. 2006;15:3273–9.
Xie Y, Varshavsky A. The E2–E3 interaction in the N-end rule pathway: the RING-H2 finger of E3 is required for the synthesis of multiubiquitin chain. EMBO J. 1999;18:6832–44.
Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Petrovski S, Wang Q, Heinzen EL, et al. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709.
Turner TN, Yi Q, Krumm N, et al. Denovo-db: a compendium of human de novo variants. Nucleic Acids Res. 2017;45(D1):D804–d11.
Halvorsen M, Petrovski S, Shellhaas R, et al. Mosaic mutations in early-onset genetic diseases. Genet Med. 2016;18:746–9.
Acuna-Hidalgo R, Bo T, Kwint MP, et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am J Hum Genet. 2015;97:67–74.
de Lange IM, Koudijs MJ, van 't Slot R, et al. Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. Epilepsia. 2018;59:690–703.
Koufaris C, Papagregoriou G, Kousoulidou L, et al. Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities. Gene. 2015;561:95–100.
Gazzellone MJ, Zhou X, Lionel AC, et al. Copy number variation in Han Chinese individuals with autism spectrum disorder. J Neurodev Disord. 2014;6:34.
Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271–2.
Smith MJ, Urquhart JE, Harkness EF, et al. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat. 2016;37:250–6.
Xiong HY, Alipanahi B, Lee LJ, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science (New York, NY). 2015;347:1254806.
Wijnen J, de Leeuw W, Vasen H, et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999;23:142–4.
Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 2016;17:241.
Iqbal Z, Vandeweyer G, van der Voet M, et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet. 2013;22:1960–70.
Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115:939–55.
Lu HC, Tan Q, Rousseaux MW, et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017;49:527–36.
Vissers LE, de Ligt J, Gilissen C, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42:1109–12.
Santen GW, Clayton-Smith J. The ARID1B phenotype: what we have learned so far. Am J Med Genet C. 2014;166c:276–89.
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 email@example.com. 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)