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Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation.
- Source :
-
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2018 Dec; Vol. 20 (12), pp. 1589-1599. Date of Electronic Publication: 2018 Apr 12. - Publication Year :
- 2018
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Alleles
Alu Elements genetics
Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology
Colorectal Neoplasms, Hereditary Nonpolyposis pathology
DNA Methylation genetics
Female
Haplotypes
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Introns genetics
Male
Middle Aged
Mutation
Pedigree
Polymorphism, Single Nucleotide genetics
Promoter Regions, Genetic genetics
Colorectal Neoplasms, Hereditary Nonpolyposis genetics
Epigenesis, Genetic
Genetic Predisposition to Disease
MutL Protein Homolog 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 20
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29790873
- Full Text :
- https://doi.org/10.1038/gim.2018.47