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.

Cologne Center for Genomics University of Cologne Köln Germany

Department of Bone Marrow Transplantation and Cancer Immunotherapy Hadassah Hebrew University Medical Center Jerusalem Israel

Department of Clinical Genetics Institute of Biology and Medical Genetics 2nd Medical School Charles University Prague Czech Republic

Department of Informatics 2nd Medical School Charles University Prague Czech Republic

Department of Medical Genetics The Children's Memorial Health Institute Warsaw Poland

Department of Paediatrics University Hospital Center Zagreb and University of Zagreb School of Medicine Zagreb Croatia

Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts United States of America

Division of Pediatric Molecular Genetics Ankara University School of Medicine Ankara Turkey

DNA Laboratory Department of Pediatric Neurology 2nd Medical School Charles University and University Hospital Motol Prague Czech Republic

Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Institute of Human Genetics Martin Luther University Halle Wittenberg Halle Germany

Institute of Medical and Human Genetics Charité Universitätsmedizin Berlin Germany

Institute of Medical Informatics and Statistics Christian Albrechts University Kiel Germany

Leipzig University Medical Center IFB AdiposityDiseases Leipzig Germany

Max Delbrück Center for Molecular Medicine Berlin Buch Germany

National Genetics Laboratory University Hospital of Obstetrics and Gynecology Medical University Sofia Bulgaria

Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Canada

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The NBN founder mutation-Evidence for a country specific difference in age at cancer manifestation

Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome