PMID- 32409512
OWN - NLM
STAT- MEDLINE
DCOM- 20210705
LR  - 20221207
IS  - 1468-6244 (Electronic)
IS  - 0022-2593 (Linking)
VI  - 57
IP  - 12
DP  - 2020 Dec
TI  - De novo mutations in the X-linked TFE3 gene cause intellectual disability with 
      pigmentary mosaicism and storage disorder-like features.
PG  - 808-819
LID - 10.1136/jmedgenet-2019-106508 [doi]
AB  - 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.
CI  - (c) Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and 
      permissions. Published by BMJ.
FAU - Lehalle, Daphne
AU  - Lehalle D
AUID- ORCID: 0000-0002-2193-8685
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France 
      daphne.lehalle@aphp.fr.
AD  - UF de Genetique Medicale, Departement de Genetique, Groupe Hospitalier 
      Pitie-Salpetriere, APHP Sorbonne Universite, Paris, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Vabres, Pierre
AU  - Vabres P
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
AD  - Centre de Reference MAGEC, Service de Dermatologie, Centre Hospitalier 
      Universitaire Dijon Bourgogne, Dijon, Bourgogne, France.
FAU - Sorlin, Arthur
AU  - Sorlin A
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Bierhals, Tatjana
AU  - Bierhals T
AD  - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 
      Martinistrasse 52, Hamburg, Germany.
FAU - Avila, Magali
AU  - Avila M
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Carmignac, Virginie
AU  - Carmignac V
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Chevarin, Martin
AU  - Chevarin M
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Torti, Erin
AU  - Torti E
AD  - GeneDx, Gaithersburg, Maryland, USA.
FAU - Abe, Yuichi
AU  - Abe Y
AD  - Division of Neurology, National Center for Child Health and Development, Tokyo, 
      Japan.
FAU - Bartolomaeus, Tobias
AU  - Bartolomaeus T
AD  - Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, 
      Germany.
FAU - Clayton-Smith, Jill
AU  - Clayton-Smith J
AD  - Genomic Medicine, Manchester Centre for Genomic Medicine, Manchester, Manchester, 
      UK.
AD  - Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and 
      Health, University of Manchester, Manchester, Greater Manchester, UK.
FAU - Cogne, Benjamin
AU  - Cogne B
AUID- ORCID: 0000-0002-5503-6292
AD  - Service de Genetique Medicale, Centre Hospitalier Universitaire de Nantes, 
      Nantes, France.
AD  - L'institut du thorax, INSERM, CNRS, Universite de Nantes, Nantes, France.
FAU - Cusco, Ivon
AU  - Cusco I
AUID- ORCID: 0000-0003-2104-9332
AD  - Department of Clinical and Molecular Genetics and Rare Disease Unit, University 
      Hospital Vall d'Hebron, Barcelona, Spain.
FAU - Duplomb, Laurence
AU  - Duplomb L
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - De Bont, Eveline
AU  - De Bont E
AD  - Department of Pediatric Oncology, Ommelander Hospital Groningen, Scheemda, 
      Groningen, The Netherlands.
FAU - Duffourd, Yannis
AU  - Duffourd Y
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Duijkers, Floor
AU  - Duijkers F
AD  - Department of Genetics, Amsterdam University Medical Centres, Amsterdam, 
      Noord-Holland, The Netherlands.
FAU - Elpeleg, Orly
AU  - Elpeleg O
AD  - Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Fattal, Aviva
AU  - Fattal A
AD  - Pediatric Neurology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty 
      of Medicine, Tel Aviv University, Tel-Aviv, Israel.
FAU - Genevieve, David
AU  - Genevieve D
AD  - Departement de Genetique Medicale, Hopital Arnaud de Villeneuve, CHRU 
      Montpellier, Montpellier, France.
FAU - Guillen Sacoto, Maria J
AU  - Guillen Sacoto MJ
AD  - GeneDx, Gaithersburg, Maryland, USA.
FAU - Guimier, Anne
AU  - Guimier A
AD  - Department of Genetics, Necker-Enfants Malades Hospitals, Paris, Ile-de-France, 
      France.
FAU - Harris, David J
AU  - Harris DJ
AD  - Division of Genomics and Genetics, Boston Children s Hospital, Boston, 
      Massachusetts, USA.
FAU - Hempel, Maja
AU  - Hempel M
AD  - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 
      Martinistrasse 52, Hamburg, Germany.
FAU - Isidor, Bertrand
AU  - Isidor B
AD  - Service de Genetique Medicale, Centre Hospitalier Universitaire de Nantes, 
      Nantes, France.
AD  - L'institut du thorax, INSERM, CNRS, Universite de Nantes, Nantes, France.
FAU - Jouan, Thibaud
AU  - Jouan T
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Kuentz, Paul
AU  - Kuentz P
AUID- ORCID: 0000-0003-2814-6303
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
AD  - Genetique Biologique Histologie, PCBio, Centre Hospitalier Universitaire de 
      Besancon, Besancon, France.
FAU - Koshimizu, Eriko
AU  - Koshimizu E
AD  - Department of Human Genetics, Yokohama City University School of Medicine 
      Graduate School of Medicine, Yokohama, Kanagawa, Japan.
FAU - Lichtenbelt, Klaske
AU  - Lichtenbelt K
AD  - Department of Genetics, University Medical Centre Utrecht Brain Centre, Utrecht, 
      Utrecht, The Netherlands.
FAU - Loik Ramey, Valerie
AU  - Loik Ramey V
AD  - Division of Genomics and Genetics, Boston Children s Hospital, Boston, 
      Massachusetts, USA.
FAU - Maik, Miriam
AU  - Maik M
AD  - Hackensack Meridian Health Inc, Edison, New Jersey, USA.
FAU - Miyakate, Sakoto
AU  - Miyakate S
AD  - Department of Human Genetics, Yokohama City University Graduate School of 
      Medicine, Yokohama, Kanagawa, Japan.
FAU - Murakami, Yoshiko
AU  - Murakami Y
AD  - Yabumoto Department of Intractable Disease Research, Research Institute for 
      Microbial Diseases, Osaka University, Suita, Osaka, Japan.
FAU - Pasquier, Laurent
AU  - Pasquier L
AD  - Service de Genetique Clinique, CLAD Ouest, CHU Rennes, Rennes, France.
FAU - Pedro, Helio
AU  - Pedro H
AD  - Hackensack Meridian Health Inc, Edison, New Jersey, USA.
FAU - Simone, Laurie
AU  - Simone L
AUID- ORCID: 0000-0002-5406-2771
AD  - Hackensack Meridian Health Inc, Edison, New Jersey, USA.
FAU - Sondergaard-Schatz, Krista
AU  - Sondergaard-Schatz K
AD  - Department of Genetic Medicine, Johns Hopkins University School of Medicine, 
      Baltimore, MD, United States.
FAU - St-Onge, Judith
AU  - St-Onge J
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
AD  - Child Health and Human Development Program, Research Institute of the McGill 
      University Health Centre, Montreal, Quebec, Canada.
FAU - Thevenon, Julien
AU  - Thevenon J
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
AD  - Departement de Genetique et Procreation, CHU Grenoble Alpes, Universite Grenoble 
      Alpes, Grenoble, France.
FAU - Valenzuela, Irene
AU  - Valenzuela I
AD  - Department of Clinical and Molecular Genetics and Rare Disease Unit, University 
      Hospital Vall d'Hebron, Barcelona, Spain.
FAU - Abou Jamra, Rami
AU  - Abou Jamra R
AD  - Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
FAU - van Gassen, Koen
AU  - van Gassen K
AD  - Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - van Haelst, Mieke M
AU  - van Haelst MM
AD  - Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The 
      Netherlands.
FAU - van Koningsbruggen, Silvana
AU  - van Koningsbruggen S
AD  - Department of Clinical Genetics, University of Amsterdam, Academic Medical 
      Centre, Amsterdam, The Netherlands.
FAU - Verdura, Edgard
AU  - Verdura E
AUID- ORCID: 0000-0003-3856-2060
AD  - Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute 
      (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
AD  - Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud 
      Carlos III, Madrid, Spain.
FAU - Whelan Habela, Christa
AU  - Whelan Habela C
AD  - Department of Neurology, John M. Freeman Pediatric Epilepsy Center, Johns Hopkins 
      Medicine, Baltimore, Maryland, USA.
FAU - Zacher, Pia
AU  - Zacher P
AD  - The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.
FAU - Riviere, Jean-Baptiste
AU  - Riviere JB
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
AD  - Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, 
      Canada.
FAU - Thauvin-Robinet, Christel
AU  - Thauvin-Robinet C
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
FAU - Betschinger, Joerg
AU  - Betschinger J
AD  - Friedrich Miescher Institute for Biomedical Research, Basel, Basel-Stadt, 
      Switzerland.
FAU - Faivre, Laurence
AU  - Faivre L
AUID- ORCID: 0000-0001-9770-444X
AD  - Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du 
      Developpement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
AD  - INSERM LNC UMR 1231, Faculte de Medecine, Universite de Bourgogne Franche-Comte, 
      Dijon, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200514
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (TFE3 protein, human)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*genetics
MH  - Child
MH  - Child, Preschool
MH  - Epilepsy/complications/*genetics/pathology
MH  - Female
MH  - Genes, X-Linked/genetics
MH  - Humans
MH  - Infant
MH  - Intellectual Disability/complications/*genetics/pathology
MH  - Male
MH  - Mosaicism
MH  - Pathology, Molecular/standards
MH  - Pigmentation Disorders/complications/*genetics/pathology
MH  - Exome Sequencing
MH  - Young Adult
OTO - NOTNLM
OT  - TFE3
OT  - intellectual disability
OT  - lysosomal metabolism
OT  - pigmentary mosaicism
OT  - storage disorder
COIS- Competing interests: MJGS and ET are employees of GeneDx, Inc.
EDAT- 2020/05/16 06:00
MHDA- 2021/07/06 06:00
CRDT- 2020/05/16 06:00
PHST- 2019/09/10 00:00 [received]
PHST- 2020/02/16 00:00 [revised]
PHST- 2020/02/22 00:00 [accepted]
PHST- 2020/05/16 06:00 [pubmed]
PHST- 2021/07/06 06:00 [medline]
PHST- 2020/05/16 06:00 [entrez]
AID - jmedgenet-2019-106508 [pii]
AID - 10.1136/jmedgenet-2019-106508 [doi]
PST - ppublish
SO  - J Med Genet. 2020 Dec;57(12):808-819. doi: 10.1136/jmedgenet-2019-106508. Epub 
      2020 May 14.