The molecular characterization of chromosome 18 abnormalities associated with specific phenotypes

Leslie Jean Sell, Thomas Jefferson University


A causal relationship between specific chromosome abnormalities and human disease and developmental disorders is well documented. We have used a fluorescent in situ hybridization (FISH) based approach to molecularly define chromosome 28 abnormalities associated with Ablepharon-Macrostomia syndrome, Tourette's syndrome and Edward's syndrome. Molecular characterization of these abnormalities will facilitate the search for candidate genes on chromosome 18 involved in these disorders. Ablepharon-Macrostomia syndrome has been reported in an infant with a complex rearrangement of chromosome 18. Multi-color FISH analysis using chromosome 18-specific regional painting probes, and single lambda phage clones previously mapped to distinct regions on chromosome 18 indicates the presence of a deletion and an inversion of chromosome 18 material. The karyotype based upon molecular cytogenetic analysis is 46,XY,-18, + ((del (18)(q21.3q23), inv(18)(q12.3q21.2). A t(7;18) chromosome translocation has been reported to segregate in a family with features of Tourette's syndrome. FISH was similarly used to precisely define the translocation breakpoint on chromosome 18, and to identify both YAC and cosmid clones spanning the translocation breakpoint on chromosome 18. Physical mapping and sequence analysis of the breakpoint region indicates that the break lies within an L1 repetitive element. In addition, sequence analysis has enabled the identification of potential coding regions surrounding the break on chromosome 18. One of these regions has been used to a isolate a partial cDNA from a brain stem cDNA library. The molecular cytogenetic determination, by FISH, of the extent of chromosome 18 duplication in six individuals with partial duplication of chromosome 18 has also been carried out. These six individuals exhibit varying degrees of severity of the classic Edward's syndrome (Trisomy 18) phenotype. The correlation of patient phenotype with the molecularly defined region of duplication in these cases, combined with four previously reported cases, has provided evidence for the presence of two noncontiguous regions on chromosome 18q critical to the Edward's syndrome phenotype. A proximal critical region appears to lie within 18q12.1-21.2 and a distal critical region within 18q22.3-qter. In addition, preliminary phenotypic mapping of individual features suggests that severe mental retardation may be associated with duplication of the region 18q12.3-q22.1. FISH analysis has provided a rapid and accurate means to define these chromosome 18 abnormalities. The initial molecular characterization of these abnormalities will lay the groundwork for the positional cloning of relevant gene(s) on chromosome 18.

Subject Area

Genetics|Molecular biology

Recommended Citation

Sell, Leslie Jean, "The molecular characterization of chromosome 18 abnormalities associated with specific phenotypes" (1997). ProQuest ETD Collection - Thomas Jefferson University. AAI9829090.