Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease

A 3-year-old boy presented with alpha-thalassaemia, dysmorphic features, and mental handicap. His younger sister is also mentally retarded, but haematologically normal. High resolution cytogenetic analysis revealed a normal karyotype in all family members. However, a combination of DNA analysis and in situ hybridisation demonstrated that the mother has a previously unsuspected balanced reciprocal translocation between the tips of the short arms of chromosomes 1 and 16, and that the alpha-globin gene complex (which maps to the tip of chromosome 16) is included in the translocated segment. Both of her children have inherited one of the translocation chromosomes in an unbalanced fashion: the boy has the derived chromosome 16, and therefore has alpha-thalassaemia, whilst the girl has the derived chromosome 1. Such cytogenetically invisible subtelomeric translocations are probably an important and hitherto unrecognised cause of genetic disease.