Stable ring chromosome 21: Molecular and clinical definition of the lesion

Ring chromosome 21 results in deletions of chromosome 21. We report on a cytogenetic and molecular analysis of a 4-generation family segregating a stable ring chromosome 21 in 4 relatives. To investigate the molecular structure of the ring chromosome, we have analyzed the DNAs of the transmitted ring in a mother and her daughter. The daughter presented at the age of 2 years with severe growth retardation and microcephaly, whereas her mother had microcephaly but normal intelligence. High resolution chromosome analysis of both cases showed the ring chromosome to be r(21)(p13q22) resulting in deletions of 21p and 21q22. The molecular content of the ring chromosome was determined using quantitative Southern blot analyses of 5 random DNA sequences and 4 expressed genes assigned to chromosome 21 and mapping in the region of q22.3. We have shown that collagen type VI, alpha 2 (COL6A2,) S100 protein, beta polypeptide (neural), (S100B), and D21S44 are present in only one copy in both ring carriers, while CRYA1, CBS, D21S43, D21S42, D21S41, and D21S39 are present in two copies. These data and the breakpoints defining the deletion in these patients show that deletion of COL6A2 and S100B is compatible with normal function and confirm the physical map of 21q22.3 by placing COL6A2, S100B, and D21S44 in very distal 21q22.3. Patients with such small deletions provide unique models for understanding the biological and clinical significance of aneuploidy for specific expressed genes.