Fish dissection of partial trisomy down's syndrome

Up to 1 in 600 individuals are born with Down's Syndrome, making the most common known genetic cause of learning disability. The classic Down's Syndrome phenotype is well documented and is associated with an increased risk of medical conditions including congenital heart disease and endocrine disturbance. We have identified a family in which the proband has the full clinical features of Down's Syndrome where repeated classical karyotyping (Giemsa banding) failed to find any evidence of trisomy. No other members of the family have a learning disability but do have a surprising degree of other clinical associates of Down's syndrome including hypothyroidism, atrial/ventricular septal defect and depression. Initial investigations of the proband using whole chromosome paints in FISH experiments indicate a partial trisomy of chromosome 21 with the extra material residing on chromosome 13. The presence of shortarm repeat material on both these acrocentric chromosomes however makes exact resolution of signals difficult. To confirm this, the proband's chromosomes have been subjected to flow cytometry in order to isolate the normal and derived chromosome 13. This material is then fluorescently labeled and reverse-FISHed to a normal cell line. In this way we aim to narrowly define the region of chromosome 21 that is in trisomy in the proband. The partial trisomy in this family is most likely the result of inheritance of the unbalanced form of a reciprocal translocation. We have also established cell lines from key relatives of the proband with clinical features associated with Down's Syndrome, who will also be studied in the same fashion.