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Phenotypes
Original Article
FOXP1-related intellectual disability syndrome: a recognisable entity
  1. Ilse Meerschaut1,2,
  2. Daniel Rochefort3,
  3. Nicole Revençu4,
  4. Justine Pètre4,
  5. Christina Corsello3,
  6. Guy A Rouleau3,
  7. Fadi F Hamdan5,
  8. Jacques L Michaud5,
  9. Jenny Morton6,
  10. Jessica Radley6,
  11. Nicola Ragge6,
  12. Sixto García-Miñaúr7,
  13. Pablo Lapunzina7,
  14. Maria Palomares Bralo7,
  15. Maria Ángeles Mori7,
  16. Stéphanie Moortgat8,
  17. Valérie Benoit8,
  18. Sandrine Mary8,
  19. Nele Bockaert2,
  20. Ann Oostra2,
  21. Olivier Vanakker1,2,
  22. Milen Velinov9,
  23. Thomy JL de Ravel10,
  24. Djalila Mekahli11,
  25. Jonathan Sebat12,
  26. Keith K Vaux13,
  27. Nataliya DiDonato14,
  28. Andrea K Hanson-Kahn15,
  29. Louanne Hudgins15,
  30. Bruno Dallapiccola16,
  31. Antonio Novelli16,
  32. Luigi Tarani17,
  33. Joris Andrieux18,
  34. Michael J Parker19,
  35. Katherine Neas20,
  36. Berten Ceulemans21,
  37. An-Sofie Schoonjans21,
  38. Darina Prchalova22,
  39. Marketa Havlovicova22,
  40. Miroslava Hancarova22,
  41. Magdalena Budisteanu23,
  42. Annelies Dheedene1,
  43. Björn Menten1,
  44. Patrick A Dion3,
  45. Damien Lederer8,
  46. Bert Callewaert1,2
  1. 1Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  2. 2Department of Pediatrics, Ghent University Hospital, Ghent, Belgium
  3. 3Montreal Neurological Institute, McGill University, Montreal, Canada
  4. 4Centre de Génétique humaine, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
  5. 5CHU Sainte-Justine Research Center, Université de Montreal, Montreal, Canada
  6. 6West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham Women’s Hospital, Edgbaston, UK
  7. 7Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
  8. 8Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
  9. 9NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
  10. 10Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
  11. 11Department of Pediatric Nephrology, University Hospital Leuven, Leuven, Belgium
  12. 12Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, USA
  13. 13Departments of Medicine and Neurosciences, UC San Diego School of Medicine, San Diego, USA
  14. 14Institut für Klinische Genetik, Technische Universität Dresden, Dresden, Deutschland
  15. 15Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, California, USA
  16. 16Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
  17. 17Department of Pediatrics and Child Neuropsychiatry, La Sapienza University, Rome, Italy
  18. 18Institut de Génétique Médicale, Hospital Jeanne de Flandre, Lille, France
  19. 19Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, UK
  20. 20Genetic Health Service NZ, Wellington, New Zealand
  21. 21Department of Neurology-Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium
  22. 22Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech
  23. 23Psychiatry Research Laboratory, Prof Dr Alexandru Obregia Clinical Hospital of Psychiatry, Bercini, Romania
  1. Correspondence to Dr Bert Callewaert, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.; Bert.Callewaert{at}Ugent.be

Abstract

Background Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.

Methods We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.

Results Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.

Conclusions FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype–phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

  • FOXP1
  • intellectual disability
  • language impairment
  • oromotor dysfunction
  • genotype-phenotype correlation

https://doi.org/10.1136/jmedgenet-2017-104579

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    Footnotes

    • Contributors We hereby declare that all authors have contributed to this work: IM and BCa contributed to the conception and design of the article, data acquisition, analysis and interpretation of the clinical, molecular and functional data, and writing of the manuscript. DL contributed to the conception and design of the article and to the acquisition of clinical and molecular patient data. DR, GAR, FFH, JLM and PAD contributed to the acquisition of the functional data, and analysis and interpretation of these data. NRe, JP, CC, JM, JR, NRa, SGM, PL, MPB, MÁM, StM, VB, SM, NB, AO, OV, MV, TJLdR, DM, JS, KKV, NDD, AKHK, LH, BD, AN, LT, JA, MJP, KN, BCe, A-SS, DP, MaH, MiH, MB, AD and BM contributed to the acquisition of clinical and molecular patient data. All authors have approved the manuscript and none have reported a conflict of interest.

    • Funding BCa is a Senior Clinical Investigator, funded by Fund for Scientific Research Flanders (FWO). This project was cofunded by FWO project G044615N and Czech grants 00064203 and NF-CZ11-PDP-3-003-2014.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Commissie voor Medische Ethiek Universitair Ziekenhuis Gent.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from and via email from decipher@sanger.ac.uk. Funding for this project was provided by the Wellcome Trust.

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