European Human Genetics Conference, May 21–24, 2016, Barcelona, Spain

Fragile X Syndrome (FXS) is caused by an expansion of CGG trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) geneon theXchromosome.Affected individuals possess over 200 copies of the CGG repeat, resulting in hypermethylation of the FMR1 promoter, which leads to epigenetic silencing of the gene and FMRP protein deficiency. Children with FXS display intellectual disabilities ranging frommild to severe, and are often diagnosedwith autism. Intriguingly, the number of trinucleotide repeats canvarybetweenandwithin tissuesof the same individual, a phenomenon known as somatic repeat instability (SRI). To elucidate the molecular mechanisms involved in hypermethylation of CGG repeats, and to explore the consequences of SRI, Hagar Mor-Shaked (Jerusalem, Israel) and colleagues have developed human FXS stem cell models. Analysis of FXS-affected human embryonic stem cell (HESC) lines showed that hypermethylation is tightly linkedtoFMR1 transcriptional inactivation, suggesting that thisepigenetic event occurs during early embryo development. Using a separate in vitromodel, data from induced pluripotent stem cells (iPSCs) derived from FXS patient fibroblasts (FXS-iPSCs) was presented. These can be differentiated into clinically-relevant cell types, such as neurons, while harboring the mutations that cause the disease. Previously, exploring the neurological features of FXS in humans relied on using difficult-toobtain postmortem brain tissue. Neurons derived from FXS-iPSCs open up the possibility of understanding the pathogenic mechanisms in more detail and potentially screening drugs to reset epigenetic modifications and correct the neurological phenotype.