Founder effect of the RETC611Y mutation in multiple endocrine neoplasia 2A in Denmark: a nationwide Study

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Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Kirstine Stochholm Krag, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Mette Gaustadnes, Torben Falck Ørntoft, Maria Rossing, Finn Cilius Nielsen, Anders Albrechtsen, Kim Brixen, Christian Godballe, Anja Lisbeth Frederiksen

BACKGROUND: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations.

METHODS: The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness.

RESULTS: A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families.

CONCLUSION: The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

OriginalsprogEngelsk
TidsskriftThyroid
Vol/bind27
Udgave nummer12
Sider (fra-til)1505-1510
Antal sider6
ISSN1050-7256
DOI
StatusUdgivet - dec. 2017

ID: 186150361