The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

Kwok, Chau-To, Vogelaar, Ingrid P., van Zelst-Stams, Wendy A., Mensenkamp, Arjen R., Ligtenberg, Marjolijn J., Rapkins, Robert W., Ward, Robyn L., Chun, Nicolette, Ford, James M., Ladabaum, Uri, McKinnon, Wendy C., Greenblatt, Marc S. and Hitchins, Megan P. (2014) The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. European Journal of Human Genetics, 22 5: 617-624. doi:10.1038/ejhg.2013.200


Author Kwok, Chau-To
Vogelaar, Ingrid P.
van Zelst-Stams, Wendy A.
Mensenkamp, Arjen R.
Ligtenberg, Marjolijn J.
Rapkins, Robert W.
Ward, Robyn L.
Chun, Nicolette
Ford, James M.
Ladabaum, Uri
McKinnon, Wendy C.
Greenblatt, Marc S.
Hitchins, Megan P.
Title The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype
Formatted title
The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype
Journal name European Journal of Human Genetics   Check publisher's open access policy
ISSN 1476-5438
1018-4813
Publication date 2014-05
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ejhg.2013.200
Open Access Status
Volume 22
Issue 5
Start page 617
End page 624
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
Formatted abstract
Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.
Keyword Lynch syndrome
MLH1
Epimutation
Founder haplotype
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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