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.

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

“…rodičů (k určení dědičné linie mutace), sourozenců a dětí. Pro no siče mutace pak nastavení vhodné on kologické prevence, a pokud jsou ve fertilním věku a plánují rodinu, pro dací, imunodeficiencí, hypersenzitivitou na ionizující záření a zvýšeným rizikem vzniku lymfoidních malignit [31]. Vět šina NBS pa cientů pochází z východní Evropy a je homozygotní pro mutaci c.657_661del (dřívější název c.657del5, p.Lys219Asnfs*16, rs587776650), která vede ke vzniku dvou trunkačních frag mentů p26 and p70 nibrinu.…”

“…Vět šina NBS pa cientů pochází z východní Evropy a je homozygotní pro mutaci c.657_661del (dřívější název c.657del5, p.Lys219Asnfs*16, rs587776650), která vede ke vzniku dvou trunkačních frag mentů p26 and p70 nibrinu. Vysoká frekvence heterozygotních nosičů této mutace (1/ 130-1/ 177) byla popsána u slovanské populace v Polsku, České re publice, Slovensku, Ukrajině a Německu, zvláště pak mezi pa cienty s onkologic kým onemocněním [31,32]. V literatuře je u nosičů této mutace opakovaně po psáno zvýšené riziko rozvoje nádorů (OR 2,79), především karcinomu prsu (OR 2,51), prostaty (OR 5,87) a lymfomů (OR 2,93) [33].…”

Exploration of genetic basis underlying individual differences in radiosensitivity within human populations using genome editing technology

“…Besides A-T, a number of hereditary disorders caused by germline mutations of the DNA repair genes have been reported, such as A-T–like disorders ( MRE11A ) [ 28 ], Nijmegen breakage syndrome (NBS; NBS1 ) [ 29 ], NBS-like disorder ( RAD50 ) [ 30 ], Riddle syndrome ( RNF168 ) [ 31 ], radiosensitive severe combined immunodeficiency ( Artemis ) [ 32 ], Lig-IV syndrome ( DNA Lig IV ) [ 33 ], and microcephalic primordial dwarfism ( XRCC4 ) [ 34 ] (Table 1 ). Moreover, heterozygous BRCA1 and BRCA2 mutations cause hereditary breast and ovarian cancers (HBOCs) [ 35 ].…”

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

“…Even heterozygous carriers of the founder mutation have an increased risk of cancer [ 8 ]. In some areas of the world, the NBN gene became the most important cancer-predisposing gene [ 7 ].…”