New Insights into Mechanisms and Consequences of Small Marker (Ring) Chromosomes. E.L. Baldwin, L.F. May, C.L. Martin, D.H. Ledbetter. Dept. Human Genetics, Emory University, Atlanta, GA.
   Supernumerary marker chromosomes occur in 1/1000 prenatal diagnostic studies and in 4/1000 individuals with mental retardation. The mechanisms of formation and clinical consequences of marker chromosomes are poorly understood. We developed a panel of 871 unique BAC clones in the pericentromeric regions of each human chromosome in order to evaluate the euchromatic makeup of marker chromosomes and to investigate their mechanism of origin. Seven small non-satellited markers derived from acrocentrics were studied, and 5 were found to be negative for the most proximal unique BAC clones, consistent with a normal phenotype. Two cases contained 1.6 and 5.9 Mb of euchromatin, including 11 and 20 predicted genes. Of 8 cases of non-acrocentric small ring marker chromosomes, 6 contain euchromatic material from either the p- or q-arm, but not both arms. This is consistent with a breakpoint within the centromeric alpha-satellite which can produce two functional chromosomes (ring and deletion), as a major mechanism of marker chromosome formation. Normal individuals may be balanced carriers of complimentary ring and deletion chromosomes, and therefore at high risk for genetically unbalanced offspring. Only 2 markers (both derived from chromosome 8) contain euchromatic material from both the p- and q-arms. Chromosome 8-derived markers are the most frequently occurring non-acrocentric ring marker chromosomes. Since breakage in both the p- and q-arms would produce only one centric chromosome product (small ring) and two acentric arms, it is possible that this mechanism is associated with a trisomy 8 conception followed by trisomy rescue by marker formation. For the above cases, marker sizes range from less than 1 Mb (containing only 3 known genes) to 15 Mb (containing over 170 known genes). Large markers can be readily detected and sized using array CGH, but small marker chromosomes containing only segmental duplications can be problematic. Although these small markers do not contain euchromatic DNA, the individual may be at risk for UPD of the normal homologs. In addition, array CGH cannot detect balanced carriers containing complimentary ring and deletion chromosomes.