FINE LOCALIZATION OF THE NIJMEGEN BREAKAGE SYNDROME GENE TO 8Q21 - EVIDENCE FOR A COMMON FOUNDER HAPLOTYPE

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorde r characterized by microcephaly, a birdlike face, growth retardation, immunodeficiency, lack of secondary sex characteristics in females, an d increased incidence of lymphoid cancers. NBS cells display a phenoty pe similar to that of cells from ataxia-telangiectasia patients, inclu ding chromosomal instability, radiation sensitivity, and aberrant cell -cycle-checkpoint control following exposure to ionizing radiation. A recent study reported genetic linkage of NBS to human chromosome 8q21, with strong linkage disequilibrium detected at marker D8S1811 in east ern European NBS families. We collected a geographically diverse group of NBS families and tested them for linkage, using an expanded panel of markers at 8q21. In this article, we report linkage of NBS to 8q21 in 6/7 of these families, with a maximum LOD score of 3.58. Significan t linkage disequilibrium was detected for 8/13 markers tested in the 8 q21 region, including D8S1811, In order to further localize the gene f or NBS, we generated a radiation-hybrid map of markers at 8q21 and con structed haplotypes based on this map. Examination of disease haplotyp es segregating in 11 NBS pedigrees revealed recombination events that place the NBS gene between D8S1757 and D8S270. A common founder haplot ype was present on 15/18 disease chromosomes from 9/11 NBS families. I nferred (ancestral) recombination events involving this common haploty pe suggest that NBS can be localized further, to an interval flanked b y markers D8S273 and D8S88.