title: The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?
abstract: The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
authors.affiliation: Department of Clinical Genetics, Institute of Biology and Medical Genetics, 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanova
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.affiliation: Department of Informatics, 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vejvalka
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Petr
authors.identifier: http://orcid.org/0000-0002-9612-8652
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: DNA Laboratory, Department of Pediatric Neurology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.affiliation: Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Igor
authors.initials: I
authors.lastname: Resnick
authors.affiliation: National Genetics Laboratory, University Hospital of Obstetrics and Gynecology, Medical University, Sofia, Bulgaria.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.affiliation: Institute of Human Genetics, Martin-Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dutrannoy
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karbasiyan
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghani
authors.affiliation: Department of Paediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: Division of Pediatric Molecular Genetics, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Institute of Medical Informatics and Statistics, Christian-Albrechts University, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.affiliation: Cologne Center for Genomics, University of Cologne, Köln, Germany.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0001-8305-7114
authors.initials: M
authors.lastname: Nothnagel
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D015331:Cohort Studies; D018153:Czech Republic; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D018703:Founder Effect; D006580:Genetic Carrier Screening; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D049932:Nijmegen Breakage Syndrome / Q000208:ethnology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012098:Reproduction / Q000235:genetics*; D018154:Slovakia
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins