TY - JOUR
T1 - Founder effect of the RETC611Y mutation in multiple endocrine neoplasia 2A in Denmark
T2 - A nationwide study
AU - Mathiesen, Jes Sloth
AU - Kroustrup, Jens Peter
AU - Vestergaard, Peter
AU - Stochholm, Kirstine
AU - Poulsen, Per Løgstrup
AU - Rasmussen, Åse Krogh
AU - Feldt-Rasmussen, Ulla
AU - Gaustadnes, Mette
AU - Ørntoft, Torben Falck
AU - Rossing, Maria
AU - Nielsen, Finn Cilius
AU - Albrechtsen, Anders
AU - Brixen, Kim
AU - Godballe, Christian
AU - Frederiksen, Anja Lisbeth
PY - 2017
Y1 - 2017
N2 - BACKGROUND: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study we reported of an unusually high prevalence (33%) of families with the C611Y mutation and hypothesized that this might be due to a founder effect. We conducted the first nationwide study of haplotypes in MEN2A families aiming to investigate 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 mutation, 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: Our 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, our 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.
AB - BACKGROUND: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study we reported of an unusually high prevalence (33%) of families with the C611Y mutation and hypothesized that this might be due to a founder effect. We conducted the first nationwide study of haplotypes in MEN2A families aiming to investigate 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 mutation, 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: Our 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, our 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.
KW - Journal Article
U2 - 10.1089/thy.2017.0404
DO - 10.1089/thy.2017.0404
M3 - Journal article
C2 - 29020875
SN - 1050-7256
VL - 27
SP - 1505
EP - 1510
JO - Thyroid
JF - Thyroid
IS - 12
ER -