Disease associated balanced chromosomal rearrangements (DBCRs) are large-scale alterations in normal genomic sequence, which occur without copy number change in a phenotypically abnormal individual. Complete ascertainment of published DBCRs was attempted via recursive searches of the literature. 775 cases were identified with 1672 breakpoints and 406 different phenotypes. Physical mapping of DBCR breakpoints has elucidated the genetic basis of Mendelian disorders in 29 cases and was the first indication of a subsequently verified disease locus in a further 30 cases. Two interesting DBCR cases, which had no cell-lines or fixed cell suspensions, were available for study: Case 1 had a t(2;12)(p25;q23.3) translocation associated with upper limb peromelia and lower limb phocomelia; Case 2 had a t(1;2)(q41;p25.3) associated with lethal bilateral renal adysplasia. In case 1, the 2p25 breakpoint was found to interrupt the ROCK2 gene, which, on the basis of the phenotype of null mice, was considered to be a poor candidate for the peromelia/phocomelia phenotype. The 12q23.3 breakpoint lay 0-25 kb from the 5’ end of the CMKLR1gene, which encodes a chemokine-like receptor, the sole ligand for which is encoded by the retinoic acid responsive gene, RARRES2. Site and stage-specific expression of both the receptor and the ligand in the developing limb bud suggested that CMKLR1 was a good candidate for a causative gene. A phenotypically similar case was screened for mutations in CMKLR1 and a candidate regulatory region, but none could be identified. A mouse model is being developed to further elucidate the developmental role of this gene. In case 2, the 2p25.3 breakpoint mapped to a gap in the genome sequence. No good candidate gene could be identified in the vicinity of this gap.