Research Studies Provide Insight Into 22q11.2 Deletion Syndrome


A spontaneous or inherited deletion of a region of chromosome 22 leads to a disorder known as the 22q11.2 deletion syndrome. This disorder is characterized by a variety of birth defects, ranging from heart malformations to autism or mental retardation, and it affects approximately one in 4,000 to 6,000 live births. The symptoms and severity of the disease depend entirely on the genes that are deleted from chromosome 22, the functions of many of which have yet to be defined.

The sites of deletion and rearrangement on chromosome 22 that lead to the 22q11.2 deletion syndrome have been mapped to repeated regions of DNA that are specific for chromosome 22. Sequence elements within these regions are capable of forming complex loop structures. Chromosomes that contain these structural elements are particularly susceptible to translocations or copy number alterations due to errors in recombination. Two research studies led by Hospital investigators and published in the April issue of Genome Research provide critical insights into the mechanisms and locations of chromosomal rearrangements at these regions of chromosome 22.

The first of these studies examines a complex case of chromosome 22 rearrangement in a female child with a small extra chromosome that contains part of chromosome 22. An analysis of the child's father's DNA showed that chromosome 22 had undergone a novel internal inversion and a translocation event that swapped genetic information between chromosomes 22 and 8. The girl was born with multiple complex symptoms as a result of this extra chromosome, including language delays, joint malformations, altered facial features, attention deficit disorder and mild learning disorders.

Using novel technologies to isolate this child's altered chromosomes and to map out their sites of rearrangement, researchers led by investigators in the laboratory of Beverly Emanuel, Ph.D., in the Division of Genetics, Anthony L. Gotter, Ph.D., and Manjunath A. Nimmakayalu, Ph.D., identified a region of chromosome 8 that was involved in the translocation event. Interestingly, this region was predicted to form a perfect loop structure similar to those identified in other rearrangement-prone regions that translocate with chromosome 22.

The authors contend that the presence of the loop structures in both chromosomes suggests a mechanism for the translocation. They theorize that the complex structure of the loop regions could delay or stall the procession of replication enzymes at both chromosomes thus inducing genomic instability and providing an opportunity for a genetic rearrangement. If this idea is confirmed it may help investigators identify and isolate additional sites of DNA rearrangement on other chromosomes that that could lead to disease.

The second study addresses the specific DNA sequences that dictate where aberrant recombination occurs at chromosome 22. Tamim H. Shaikh, Ph.D., and Sulagna C. Saitta, M.D., Ph.D., Division of Genetics, examined two uncommon chromosome 22 distal deletions and characterized them at the sequence level. This is the first study to characterize chromosome 22 breakpoints at the molecular level and to identify a distal region of chromosome 22 that contributes to human genomic disorders. A specific sequence module, the "BCRL module," was identified within the regions of chromosome 22 where the breakpoints were. The BCRL module is also present in other regions of chromosome 22 that contain well-described deletions, suggesting that it may mediate those rearrangements as well. Additionally, they found evidence of sequence elements that can potentially form loop structures close to the deletion breakpoints in one of their patients. Dr. Shaikh's depiction of the findings is featured on the cover of the April 2007 issue of Genome Research.

The results of these studies provide critical insight into the mechanism of recombination at chromosome 22 and have significant implications for the diagnosis of other genetic disorders. The presence of similar structural and sequence components in other recombination-prone chromosomal regions could lead to the identification of rearrangements underlying other genetic disorders and in chromosome evolution.

Children's Hospital co-authors for these publications include Ron O'Connor, G. Reza Jalali, April M. Hacker, Jacob Vorstman, M.D., Danielle C. Duffy, Livija Medne and Elizabeth Geiger. Research was performed in the labs of Beverly S. Emanuel, Ph.D., and Sulagna C. Saitta, M.D., Ph.D.