Molecular and cytogenetic analysis of the 18q-syndrome
18q- syndrome is a partial aneuploidy syndrome caused by the deletion of part of the long arm of chromosome 18. Typically patients with this syndrome exhibit decreased growth, characteristic facial dysmorphologies, extremity abnormalities, hearing loss, developmental delay and mental retardation. However, the clinical presentation of this syndrome is very variable and many of the patients only exhibit a small number of the features associated with the syndrome. A study was initiated to attempt to determine the molecular basis of the 18q- syndrome and also the clinical variation exhibited by 18q- syndrome patients. A large number of 18q- syndrome patients were analyzed by molecular cytogenetics to determine the locations of their breakpoints on chromosome 18. Molecular cytogenetic analysis was carried out by use of fluorescence in situ hybridization, using a large number of chromosome 18-specific lambdaphage clones, that had previously been mapped to specific regions of chromosome 18. In addition the parental origin of the deletion possessed by some of the patients was also determined. This was done by studying the inheritance patterns of microsatellite sequences on the long arm of chromosome 18. The clinical features exhibited by each of the patients was then compared to the size of the deletion and also the parental origin (if known) to determine if any correlation existed between the size or parental origin of the deletion and the severity of the phenotype. No correlation was found between the parental origin of the deletion and the clinical features of the patients. Furthermore, no correlation was found between the size of the deletion and the severity of the phenotype. Instead the results suggest that a critical region, responsible for all of the classical features of 18q- syndrome, lies in the very distal part of the long arm of chromosome 18, within 18q23. The size of the critical region is estimated to be 6Mb. Deletion of this region results in a susceptibility to all of the features of 18q- syndrome, but the expression of individual features appears to be governed by other factors, such as genetic background or environmental factors. To allow the analysis of the critical region at a molecular level, physical mapping was performed. A YAC and cosmid contig of the region was constructed. Gaps in the contig were filled in by utilizing end-clones of YACs that flanked the gaps. This was either done by using the end-clones to initiate cosmid walking or by designing primers based on the sequence of the end-clones and using these to screen YAC libraries. Several methods were utilized to attempt to identify potential candidate genes that may play a role in the etiology of the syndrome. Three known genes were mapped to the critical region by PCR analysis, a further five novel cDNAs were identified by cDNA selection and four putative exons were identified by island rescue PCR.
Strathdee, Gordon Ronald, "Molecular and cytogenetic analysis of the 18q-syndrome" (1997). ETD Collection for Thomas Jefferson University. AAI9703677.