De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

  • Am J Hum Genet. 2018 Aug 2;103(2):305-316. doi: 10.1016/j.ajhg.2018.07.003.
Anne Gregor  1 ,  Lynette G Sadleir  2 ,  Reza Asadollahi  3 ,  Silvia Azzarello-Burri  3 ,  Agatino Battaglia  4 ,  Lilian Bomme Ousager  5 ,  Paranchai Boonsawat  3 ,  Ange-Line Bruel  6 ,  Rebecca Buchert  7 ,  Eduardo Calpena  8 ,  Benjamin Cogné  9 ,  Bruno Dallapiccola  10 ,  Felix Distelmaier  11 ,  Frances Elmslie  12 ,  Laurence Faivre  13 ,  Tobias B Haack  7 ,  Victoria Harrison  14 ,  Alex Henderson  15 ,  David Hunt  14 ,  Bertrand Isidor  16 ,  Pascal Joset  3 ,  Satoko Kumada  17 ,  Augusta M A Lachmeijer  18 ,  Melissa Lees  19 ,  Sally Ann Lynch  20 ,  Francisco Martinez  21 ,  Naomichi Matsumoto  22 ,  Carey McDougall  23 ,  Heather C Mefford  24 ,  Noriko Miyake  22 ,  Candace T Myers  24 ,  Sébastien Moutton  13 ,  Addie Nesbitt  25 ,  Antonio Novelli  10 ,  Carmen Orellana  21 ,  Anita Rauch  3 ,  Monica Rosello  21 ,  Ken Saida  22 ,  Avni B Santani  26 ,  Ajoy Sarkar  27 ,  Ingrid E Scheffer  28 ,  Marwan Shinawi  29 ,  Katharina Steindl  3 ,  Joseph D Symonds  30 ,  Elaine H Zackai  23 ,  University of Washington Center for Mendelian Genomics ,  DDD Study  31 ,  André Reis  1 ,  Heinrich Sticht  32 ,  Christiane Zweier  33
Affiliations
  • 1. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 2. Department of Paediatrics and Child Health, University of Otago, Wellington 6242, New Zealand.
  • 3. Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
  • 4. Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, 56128 Calambrone, Pisa, Italy.
  • 5. Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
  • 6. INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21079 Dijon, France.
  • 7. Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
  • 8. Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
  • 9. Department of Medical Genetics, CHU Nantes, 44093 Nantes, France; l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France.
  • 10. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • 11. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
  • 12. South West Thames Regional Genetics Service, St. George's, University of London, London SW17 0RE, UK.
  • 13. INSERM U1231, LNC UMR1231 GAD, Burgundy University, 21079 Dijon, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France.
  • 14. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
  • 15. Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne NE1 3BZ, UK.
  • 16. Department of Medical Genetics, CHU Nantes, 44093 Nantes, France.
  • 17. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo 183-0042, Japan.
  • 18. Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, the Netherlands.
  • 19. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 20. Dept of Clinical Genetics, Temple Street Children's Hospital Dublin 1, D12 V004 Dublin, Ireland.
  • 21. Unidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, 46026 Valencia, Spain.
  • 22. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 23. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 24. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 25. Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 26. Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 27. Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.
  • 28. Departments of Medicine and Paediatrics, Austin Health and Royal Children's Hospital, The University of Melbourne, Parkville, VIC 3050, Australia.
  • 29. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 30. Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow G51 4TF, UK.
  • 31. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 32. Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 33. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: [email protected].
PMID: 30057029 DOI: 10.1016/j.ajhg.2018.07.003
Abstract

Next-generation Sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome Sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin Ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various Other features.

Keywords
FBXO11; intellectual disability; neurodevelopmental disorder.