Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark

A nationwide study

Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Kirstine Stochholm, 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

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalThyroid
Volume27
Issue number12
Pages (from-to)1505-1510
ISSN1050-7256
DOIs
Publication statusPublished - 2017

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Founder Effect
Denmark
Mutation
Germ-Line Mutation
Haplotypes
Single Nucleotide Polymorphism

Keywords

  • Journal Article

Cite this

Mathiesen, J. S., Kroustrup, J. P., Vestergaard, P., Stochholm, K., Poulsen, P. L., Rasmussen, Å. K., ... Frederiksen, A. L. (2017). Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark: A nationwide study. Thyroid, 27(12), 1505-1510. https://doi.org/10.1089/thy.2017.0404
Mathiesen, Jes Sloth ; Kroustrup, Jens Peter ; Vestergaard, Peter ; Stochholm, Kirstine ; Poulsen, Per Løgstrup ; Rasmussen, Åse Krogh ; Feldt-Rasmussen, Ulla ; Gaustadnes, Mette ; Ørntoft, Torben Falck ; Rossing, Maria ; Nielsen, Finn Cilius ; Albrechtsen, Anders ; Brixen, Kim ; Godballe, Christian ; Frederiksen, Anja Lisbeth. / Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark : A nationwide study. In: Thyroid. 2017 ; Vol. 27, No. 12. pp. 1505-1510.
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title = "Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark: A nationwide study",
abstract = "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.",
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Mathiesen, JS, Kroustrup, JP, Vestergaard, P, Stochholm, K, Poulsen, PL, Rasmussen, ÅK, Feldt-Rasmussen, U, Gaustadnes, M, Ørntoft, TF, Rossing, M, Nielsen, FC, Albrechtsen, A, Brixen, K, Godballe, C & Frederiksen, AL 2017, 'Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark: A nationwide study', Thyroid, vol. 27, no. 12, pp. 1505-1510. https://doi.org/10.1089/thy.2017.0404

Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark : A nationwide study. / Mathiesen, Jes Sloth; Kroustrup, Jens Peter; Vestergaard, Peter; Stochholm, Kirstine; Poulsen, Per Løgstrup; Rasmussen, Åse Krogh; Feldt-Rasmussen, Ulla; Gaustadnes, Mette; Ørntoft, Torben Falck; Rossing, Maria; Nielsen, Finn Cilius; Albrechtsen, Anders; Brixen, Kim; Godballe, Christian; Frederiksen, Anja Lisbeth.

In: Thyroid, Vol. 27, No. 12, 2017, p. 1505-1510.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Founder effect of the RET C611Y 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

VL - 27

SP - 1505

EP - 1510

JO - Thyroid

JF - Thyroid

SN - 1050-7256

IS - 12

ER -

Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK et al. Founder effect of the RET C611Y mutation in multiple endocrine neoplasia 2A in Denmark: A nationwide study. Thyroid. 2017;27(12):1505-1510. https://doi.org/10.1089/thy.2017.0404