PT - JOURNAL ARTICLE AU - Daphné Lehalle AU - Pierre Vabres AU - Arthur Sorlin AU - Tatjana Bierhals AU - Magali Avila AU - Virginie Carmignac AU - Martin Chevarin AU - Erin Torti AU - Yuichi Abe AU - Tobias Bartolomaeus AU - Jill Clayton-Smith AU - Benjamin Cogné AU - Ivon Cusco AU - Laurence Duplomb AU - Eveline De Bont AU - Yannis Duffourd AU - Floor Duijkers AU - Orly Elpeleg AU - Aviva Fattal AU - David Geneviève AU - Maria J Guillen Sacoto AU - Anne Guimier AU - David J Harris AU - Maja Hempel AU - Bertrand Isidor AU - Thibaud Jouan AU - Paul Kuentz AU - Eriko Koshimizu AU - Klaske Lichtenbelt AU - Valerie Loik Ramey AU - Miriam Maik AU - Sakoto Miyakate AU - Yoshiko Murakami AU - Laurent Pasquier AU - Helio Pedro AU - Laurie Simone AU - Krista Sondergaard-Schatz AU - Judith St-Onge AU - Julien Thevenon AU - Irene Valenzuela AU - Rami Abou Jamra AU - Koen van Gassen AU - Mieke M van Haelst AU - Silvana van Koningsbruggen AU - Edgard Verdura AU - Christa Whelan Habela AU - Pia Zacher AU - Jean-Baptiste Rivière AU - Christel Thauvin-Robinet AU - Joerg Betschinger AU - Laurence Faivre TI - <em>De novo</em> mutations in the X-linked <em>TFE3</em> gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features AID - 10.1136/jmedgenet-2019-106508 DP - 2020 Dec 01 TA - Journal of Medical Genetics PG - 808--819 VI - 57 IP - 12 4099 - http://jmg.bmj.com/content/57/12/808.short 4100 - http://jmg.bmj.com/content/57/12/808.full SO - J Med Genet2020 Dec 01; 57 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.