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.
- intellectual disability
- lysosomal metabolism
- pigmentary mosaicism
- storage disorder
Statistics from Altmetric.com
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.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.