Incidence of the major Nijmegen breakage syndrome (NBS) mutation 657del5 in Czech Republic, Poland and Ukraine. R. Varon¹, E. Seemanova², K. Chrzanowska³, D. Abramczuk³, O. Hnateyko⁴, K. Sperling¹, A. Reis^1,5. 1) Institute of Human Genetics, Humboldt University, Charite, Berlin, Germany; 2) Department of Medical Genetics, Charles University, Prague, Czech Republic; 3) Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland; 4) Scientific-Research Institute of Hereditory Pathology, Lvov, Ukraine; 5) Mikrosatellitenzentrum, Max-Delbrck Center, Berlin, Germany.

   Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome, characterised by microcephaly, bird-like face, growth retardation, radiosensitivity, immunodeficiency and high susceptibility to lymphoid malignancy. Most patients are of Slavic ancestry. Recently we cloned the NBS1 gene which codes for nibrin, a member of the RAD50 protein complex of DNA double-strand break repair and recombination. We identified a total of 7 truncating mutations in different NBS patients, the majority being homozygous for mutation 657del5 in exon 6. We found this mutation in 68 unrelated NBS patients. Based on epidemiological data it has been proposed that NBS heterozygotes also have an elevated incidence of malignancies. In order to determine the population incidence of NBS mutations we now undertook a study to estimate the frequency of the 657del5 mutation in the Czech Republic and Poland. We analysed 1713 randomly selected, anonymous Guthrie cards from new-borns, 645 from Czech Republic 568 from Poland and 500 from Ukraine. Using PCR-SSCP analysis followed by direct sequencing of positive samples we identified a total of 11 heterozygotes (5, 3 and 3, respectively), corresponding to an incidence of approx.1 in 156 in the three populations tested. If the elevated cancer risk for NBS heterozygotes is confirmed this high carrier frequency would mean, that this NBS mutation contributes considerably to the cancer load of both populations investigated. Other non-founder mutations in NBS1 could also contribute to the cancer frequency in other populations and confirm the hypothesis that nibrin acts as a tumour-suppressor. We now plan to asses the exact cancer risk for these individuals trough epidemiological studies.