Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man

Disease associated balanced chromosomal rearrangements (DBCRs), which trunc ate, delete, or otherwise inactivate specific genes, have been instrumental for positional cloning of many disease genes. A network of cytogenetic lab oratories, Mendelian Cytogenetics Network (MCN), has been established to fa cilitate the identification and mapping of DBCRs. To get an estimate of the potential of this approach, we surveyed all cytogenetic archives in Denmar k and southern Sweden, with a population of similar to6.6 million. The nine laboratories have performed 71 739 postnatal cytogenetic tests. Excluding Robertsonian translocations and chromosome 9 inversions, we identified 216 DBCRs (similar to0.3%),including a minimum estimate of 114 de novo reciproc al translocations (0.16%) and eight de novo inversions (0.01%). Altogether, this is six times more frequent than in the general population, suggesting a causal relationship with the traits involved in most of these cases. Of the identified cases, only 25 (12%) have been published, including 12 cases with known syndromes and 13 cases with unspecified mental retardation/cong enital malformations. The remaining DBCRs were associated with a plethora o f traits including mental retardation, dysmorphic features, major congenita l malformations, autism, and male and female infertility. Several of the un published DBCRs defined candidate breakpoints for nail-patella, Prader-Will i, and Schmidt syndromes, ataxia, and ulna aplasia. The implication of the survey is apparent when compared with MCN; altogether, the 292 participatin g laboratories have performed >2.5 million postnatal analyses, with an esti mated similar to 7500 DBCRs stored in their archives, of which more than ha lf might be causative mutations. In addition, an estimated 450-500 novel ca ses should be detected each year. Our data illustrate that DBCRs and MCN ar e resources for large scale establishment of phenotype-genotype relationshi ps in man.