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De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features
  1. Daphné Lehalle1,2,3,
  2. Pierre Vabres1,3,4,
  3. Arthur Sorlin1,3,
  4. Tatjana Bierhals5,
  5. Magali Avila3,
  6. Virginie Carmignac1,3,
  7. Martin Chevarin3,
  8. Erin Torti6,
  9. Yuichi Abe7,
  10. Tobias Bartolomaeus8,
  11. Jill Clayton-Smith9,10,
  12. Benjamin Cogné11,12,
  13. Ivon Cusco13,
  14. Laurence Duplomb3,
  15. Eveline De Bont14,
  16. Yannis Duffourd1,3,
  17. Floor Duijkers15,
  18. Orly Elpeleg16,
  19. Aviva Fattal17,
  20. David Geneviève18,
  21. Maria J Guillen Sacoto6,
  22. Anne Guimier19,
  23. David J Harris20,
  24. Maja Hempel5,
  25. Bertrand Isidor11,12,
  26. Thibaud Jouan3,
  27. Paul Kuentz3,21,
  28. Eriko Koshimizu22,
  29. Klaske Lichtenbelt23,
  30. Valerie Loik Ramey20,
  31. Miriam Maik24,
  32. Sakoto Miyakate25,
  33. Yoshiko Murakami26,
  34. Laurent Pasquier27,
  35. Helio Pedro24,
  36. Laurie Simone24,
  37. Krista Sondergaard-Schatz28,
  38. Judith St-Onge3,29,
  39. Julien Thevenon1,3,30,
  40. Irene Valenzuela13,
  41. Rami Abou Jamra31,
  42. Koen van Gassen32,
  43. Mieke M van Haelst32,
  44. Silvana van Koningsbruggen33,
  45. Edgard Verdura34,35,
  46. Christa Whelan Habela36,
  47. Pia Zacher37,
  48. Jean-Baptiste Rivière3,38,
  49. Christel Thauvin-Robinet1,3,
  50. Joerg Betschinger39,
  51. Laurence Faivre1,3
  1. 1Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France
  2. 2UF de Génétique Médicale, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP Sorbonne Université, Paris, France
  3. 3INSERM LNC UMR 1231, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France
  4. 4Centre de Référence MAGEC, Service de Dermatologie, Centre Hospitalier Universitaire Dijon Bourgogne, Dijon, Bourgogne, France
  5. 5Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, Germany
  6. 6GeneDx, Gaithersburg, Maryland, USA
  7. 7Division of Neurology, National Center for Child Health and Development, Tokyo, Japan
  8. 8Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
  9. 9Genomic Medicine, Manchester Centre for Genomic Medicine, Manchester, Manchester, UK
  10. 10Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, Greater Manchester, UK
  11. 11Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France
  12. 12L'institut du thorax, INSERM, CNRS, Université de Nantes, Nantes, France
  13. 13Department of Clinical and Molecular Genetics and Rare Disease Unit, University Hospital Vall d'Hebron, Barcelona, Spain
  14. 14Department of Pediatric Oncology, Ommelander Hospital Groningen, Scheemda, Groningen, The Netherlands
  15. 15Department of Genetics, Amsterdam University Medical Centres, Amsterdam, Noord-Holland, The Netherlands
  16. 16Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  17. 17Pediatric Neurology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
  18. 18Departement de Génétique Medicale, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France
  19. 19Department of Genetics, Necker-Enfants Malades Hospitals, Paris, Île-de-France, France
  20. 20Division of Genomics and Genetics, Boston Children s Hospital, Boston, Massachusetts, USA
  21. 21Génétique Biologique Histologie, PCBio, Centre Hospitalier Universitaire de Besancon, Besancon, France
  22. 22Department of Human Genetics, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
  23. 23Department of Genetics, University Medical Centre Utrecht Brain Centre, Utrecht, Utrecht, The Netherlands
  24. 24Hackensack Meridian Health Inc, Edison, New Jersey, USA
  25. 25Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  26. 26Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
  27. 27Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France
  28. 28Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
  29. 29Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
  30. 30Département de Génétique et Procréation, CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France
  31. 31Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
  32. 32Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  33. 33Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands
  34. 34Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
  35. 35Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
  36. 36Department of Neurology, John M. Freeman Pediatric Epilepsy Center, Johns Hopkins Medicine, Baltimore, Maryland, USA
  37. 37The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
  38. 38Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
  39. 39Friedrich Miescher Institute for Biomedical Research, Basel, Basel-Stadt, Switzerland
  1. Correspondence to Dr Daphné Lehalle, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon et Université de Bourgogne, Dijon, France; daphne.lehalle{at}


Introduction Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.

Materials and methods Subsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.

Results We describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.

Conclusion This series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

  • TFE3
  • intellectual disability
  • lysosomal metabolism
  • pigmentary mosaicism
  • storage disorder
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  • Contributors DL wrote the paper. AS, MA, VC, MC, ET, BC, IC, LD, YD, OE, MJGS, TJ, PK, JS-O, JT, KvG, EV, BM, ToBa and RAJ performed and interpreted the molecular data. TaBi, JC-S, EDB, FD, AF, DG, AG, DJH, MH, BI, KL, VLR, LP, KS-S, IV, MMvH, SvK, CWH, YA, EK, MM, SM, YM, HP, LS and PZ referred the patients. PV, JB, CT-R, JB-R and LF planned and supervised the work.

  • Funding This work was funded by the Agence Nationale de la Recherche (ANR-13-PDOC-0029 to J-BR), the Programme Hospitalier de Recherche Clinique National 2010 (NCT01950975 to PV), the Conseil Régional de Bourgogne through the Plan d'actions Régional pour l'innovation and the European Union through the PO FEDER-FSE Bourgogne 2014/2020 programmes to the GAD team. This study was supported by the URDCat programme (PERIS SLT002/16/00174). EV was funded by a grant from the Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811).

  • Competing interests MJGS and ET are employees of GeneDx, Inc.

  • Patient consent for publication Parental/guardian consent obtained.

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

  • Data availability statement Data are available in a public, open access repository.

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