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.
Highlights
Nijmegen Breakage Syndrome (NBS [MIM: 251260]) is a chromosome instability disorder characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to Xirradiation, and an exceptionally high risk for lymphoid malignancy [1,2,3]
The corresponding gene product, nibrin, is part of the trimeric MRE11/RAD50 complex that is involved in the repair of DNA double strand breaks (DSBs) and in their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination
We estimated the age of the NBN c.657del5 founder mutation and sought for an explanation of its widespread occurrence in Slavic populations
Summary
Nijmegen Breakage Syndrome (NBS [MIM: 251260]) is a chromosome instability disorder characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to Xirradiation, and an exceptionally high risk for lymphoid malignancy [1,2,3]. The corresponding gene product, nibrin, is part of the trimeric MRE11/RAD50 complex that is involved in the repair of DNA double strand breaks (DSBs) and in their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination (summarized in [7, 8]) This multi-functionality explains the complex NBS phenotype, the very high incidence of malignancies that form the major cause of early death amongst NBS patients [2]. To the best of our knowledge, NBN c.657del is the only Slavic founder mutation of high prevalence described so far. It obviously predated the medieval migration of the Slavic tribes. From the evolutionary history of Y-chromosomal STR haplotype R1a, the Russian Plain branch (including proto-Slavic tribes) living in present-day Russia, Ukraine, Belarus, Poland and the Baltic countries is estimated to have appeared about 4,600 years ago [14]
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