Title: The health of the Roma people: a review of the published literature
Abstract: <h3>Introduction</h3> 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 (<i>TFE3</i>) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions. <h3>Materials and methods</h3> Subsequent data sharing allowed the clustering of <i>de novo TFE3</i> variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM. <h3>Results</h3> We describe the detailed clinical and molecular data of 17 individuals harbouring a <i>de novo TFE3</i> variant, including the patients that initially allowed reporting <i>TFE3</i> 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. <h3>Conclusion</h3> This series further delineates the specific storage disorder-like phenotype with PM ascribed to <i>de novo TFE3</i> 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.