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Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis

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  2. Correction: Educational delay and attainment in persons with neurofibromatosis 1 in Denmark

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  3. The Global State of the Genetic Counseling Profession

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  4. A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course

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  1. Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform

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  2. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

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  3. Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants

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  4. Osteogenesis imperfecta and the teeth, eyes, and ears-a study of non-skeletal phenotypes in adults

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  • Philip Farrell
  • Claude Férec
  • Milan Macek
  • Thomas Frischer
  • Sabine Renner
  • Katharina Riss
  • David Barton
  • Teresa Repetto
  • Maria Tzetis
  • Karine Giteau
  • Morten Duno
  • Melissa Rogers
  • Hara Levy
  • Mourad Sahbatou
  • Yann Fichou
  • Cédric Le Maréchal
  • Emmanuelle Génin
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The high incidence of cystic fibrosis (CF) is due to the frequency of the c.1521_1523delCTT variant in the cystic fibrosis transmembrane conductance regulator (CFTR), but its age and origin are uncertain. This gap limits attempts to shed light on the presumed heterozygote selective advantage that accounts for the variant's high prevalence among Caucasian Europeans and Europe-derived populations. In addition, explaining the nature of heterozygosity to screened individuals with one c.1521_1523delCTT variant is challenging when families raise questions about these issues. To address this gap, we obtained DNA samples from 190 patients bearing c.1521_1523delCTT and their parents residing in geographically distinct European populations plus a Germany-derived population in the USA. We identified microsatellites spanning CFTR and reconstructed haplotypes at 10 loci to estimate the time/age of the most recent common ancestor (tMRCA) with the Estiage program. We found that the age estimates differ between northwestern populations, where the mean tMRCA values vary between 4600 and 4725 years, and the southeastern populations where c.1521_1523delCTT seems to have been introduced only about 1000 years ago. The tMRCA values of Central Europeans were intermediate. Thus, our data resolve a controversy by establishing an early Bronze Age origin of the c.1521_1523delCTT allele and demonstrating its likely spread from northwest to southeast during ancient migrations. Moreover, taking the archeological record into account, our results introduce a novel concept by suggesting that Bell Beaker folk were the probable migrating population responsible for the early dissemination of c.1521_1523delCTT in prehistoric Europe.

Original languageEnglish
JournalEuropean journal of human genetics : EJHG
Volume26
Issue number12
Pages (from-to)1832-1839
Number of pages8
ISSN1018-4813
DOIs
Publication statusPublished - Dec 2018

ID: 56214236