• Molecular cytogenetic analysis of inv dup(15) chromosomes

      Leana-Cox, Julie; Schwartz, Stuart, 1951- (1993)
      An inverted duplication of chromosome 15 (inv dup(15)) is the most common supernumerary ("marker") chromosome, comprising approximately 40% of reported cases. Clinical and morphological heterogeneity among cases of inv dup(15) is evident: smaller markers are more often associated with a normal phenotype, while larger ones are frequently found in patients with mental retardation and physical anomalies. However, no studies have demonstrated an association between the presence of specific chromosome 15 subregions and abnormal phenotypic outcome. In the present study, 27 cases of inv dup(15) were analyzed using fluorescence in situ hybridization (FISH) to delineate the extent of duplicated 15q material. To provide DNA probes for this analysis, six cosmids mapping to proximal 15q were isolated from a chromosome 15-specific library. Four additional DNA probes mapping to this region were obtained. Three different breakpoints were identified based on hybridization results using these 10 DNA probes, dividing cases into 3 types. Breakpoints in the majority of larger inv dup(15) chromosomes (Types 2 and 3) are different from the distal breakpoint in Prader-Willi (PWS) and Angelman syndrome (AS) deletions. To investigate mechanisms responsible for the formation of inv dup(15) chromosomes, cytological heteromorphisms indicating whether each marker chromosome was derived from a single or two different chromosome 15 homologs were studied. Fifteen of 21 markers (71%) displayed morphological differences between the two short arms within each inv dup(15) chromosome, consistent with the hypothesis that a primary mechanism of formation is a U-type exchange event between nonsister chromatids during meiosis. To evaluate genotype-phenotype associations, patients with known phenotypes were grouped based on the presence or absence of mental retardation. A significant association was observed between the presence of the PWS/AS chromosomal region (PWCR) and mental retardation (N = 16, p {dollar}<{dollar} 0.01). Patients with Type 2 markers displayed phenotypes comparable to those with Type 3 markers, suggesting that the additional genetic material in Type 3 markers did not contribute to the phenotype. This is the largest study of inv dup(15) chromosomes to demonstrate molecular heterogeneity among cytogenetically identical cases (Types 2 and 3), and the first study of any constitutive marker chromosome to report a significant association between the presence of specific subchromosomal regions and an abnormal phenotype.