Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation - PubMed (original) (raw)

. 2018 Dec;20(12):1589-1599.

doi: 10.1038/gim.2018.47. Epub 2018 Apr 12.

Cathy Flament 2, Tonio Lovecchio 2, Lucie Delattre 2, Emilie Ait Yahya 3, Stéphanie Baert-Desurmont 4, Nelly Burnichon 5, Myriam Bronner 6, Odile Cabaret 7, Sophie Lejeune 8, Rosine Guimbaud 9, Gilles Morin 10, Jacques Mauillon 11, Philippe Jonveaux 12, Pierre Laurent-Puig 13, Thierry Frébourg 4, Nicole Porchet 14, Marie-Pierre Buisine 14

Affiliations

• PMID: 29790873
• DOI: 10.1038/gim.2018.47

Free article

Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation

Julie Leclerc et al. Genet Med. 2018 Dec.

Free article

Abstract

Purpose: Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far.

Methods: We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations.

Results: This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5'-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription.

Conclusion: This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.

Keywords: Lynch syndrome; MLH1 promoter methylation; constitutional epimutation; secondary epimutation; structural variants.

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