6 - Re-Examination of Danish Carriers of Balanced Chromosomal Inversions

Abstract

Molecular mapping of balanced chromosomal rearrangements (BCRs) such as translocations and inversions is a well-known strategy for identifying new disease-associated genes, especially genes involved in early-onset and monogenic disorders. This strategy is especially applicable in Denmark, where we can link genomic and epidemiological data from nationwide medical registries. In a previous clinical and molecular re-examination of Danish translocation carriers and carriers of de novo BCRs using next-generation mate-pair sequencing, we have been able to identify new candidate disease-genes for both early and later onset disorders, as well as for monogenic and complex disorders. By linking medical registry and questionnaire data from >500 consented carriers of rare inversions, with mate-pair sequencing of 142 selected carriers, we have identified 60 unique rearrangements (corresponding to 121 inversion breakpoints). Consistent with previous findings, the breakpoints truncate all compartments of the genome, including protein-coding genes, non-coding genes, and known and candidate long-range acting regulatory domains. Some of the inversions segregate in surprisingly large families, and we have identified 10 founder inversions in the Danish population. In several of the large inversion families, we observe an apparent excess of neuropsychiatric disorders, where the molecular data link the phenotype to either a specific candidate gene, or to a candidate domain for long-range position effects. Thus, a paracentric founder inversion on chromosome 12p verified in 120 individuals from 36 families (including one homozygous individual), truncate a gene known to be associated with cardiac, skeletal and potentially cognitive problems. This unique cohort will allow a unique, unbiased register-based epidemiological assessment of the clinical significance of the 12p-founder inversion. Furthermore, the family histories indicate that this 12p-founder inversion could be present in North-America.