Dámaso, EstelaCastillejo, AdelaArias, María del MarCanet Hermida, JúliaNavarro, MatildeValle Domínguez, Jesús delCampos, OlgaFernández, AnnaMarín, FátimaTurchetti, DanielaGarcía Díaz, Juan de DiosLázaro García, ConxiGenuardi, MaurizioRueda, DanielAlonso, ÁngelSoto, Jose LuisHitchins, MeganPineda Riu, MartaCapellá, G. (Gabriel)2020-11-172020-11-172018-100007-0920https://hdl.handle.net/2445/172157BACKGROUND: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. METHODS: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. RESULTS: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter- generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.10 p.application/pdfengcc by-nc-sa (c) Dámaso et al., 2018http://creativecommons.org/licenses/by-nc-sa/3.0/es/EpigènesiMutació (Biologia)EpigenesisMutation (Biology)info:eu-repo/semantics/article6860722020-11-17info:eu-repo/semantics/openAccess30283143