Dr. Ledbetter’s group is examining the contribution of rare de novo genetic changes to autism and other neurodevelopmental and psychiatric conditions. They have found clinically relevant copy number variations, most often de novo events, in about 10% of patients with autism, a result that confirms earlier findings reported by other investigators.
Routine chromosome analysis is particularly limited in its ability to detect submicroscopic microduplications and microdeletions, chromosomal rearrangements that represent the genetic basis of many medical conditions, and these chromosomal changes were shown, by several authors, to be underdetected and under-diagnosed.
“For clinicians and families, the development of CGH arrays has revolutionized the recognition of all these variants,” says Sau Wai Cheung, Ph.D., professor and director of the cytogenetics laboratory at Baylor College of Medicine.
Dr. Cheung and collaborators used high-resolution array CGH to explore the genomic basis of Phelan-McDermid or 22q13.3 deletion syndrome, a rare genetic condition characterized by neurodevelopmental delay, delayed speech, hypotonia, and minor dysmorphic craniofacial features.
On a group of 10 patients, the authors characterized the boundaries of the deletions associated with this condition and reported heterogeneous pathological rearrangements that deleted between 3 and approximately 90 genes. This result illustrated the utility of array CGH in defining the extent of deletions and characterizing their breakpoints and highlighted their important clinical applications in unveiling genotype-phenotype correlations.
In another recent study, Dr. Cheung and colleagues demonstrated the strength conferred by the combined use of array CGH and fluorescence in situ hybridization when exploring insertional translocations, a type of complex genomic rearrangement requiring at least three chromosomal breaks.
By using this combined approach to analyze samples from 18,000 patients, the authors unveiled 40 insertional translocations and reported that four of them, which resulted in deletions and most likely had pathogenic significance, were inherited from a parental balanced insertion. This finding drastically changed the implications for estimating the recurrence risk and for conducting genetic counseling in the respective families.
While new genome-wide association studies are reported on a monthly basis, understanding their significance could open major difficulties for investigators. “We are at exciting times, but there are a lot of things we don’t know. While array CGH will be here for a while, the real challenge is how to interpret the information that is generated, and this will represent the bottleneck,” predicts Dr. Cheung.
From its establishment as a field in 1956, human cytogenetics has witnessed profound transformations, first through the introduction of chromosome banding, and subsequently with the development of radioactive and fluorescence in situ hybridization, followed by comparative genomic hybridization.
As one of the most recent and sophisticated additions to this set of tools, array CGH promises to unveil a previously undetectable facet of chromosome organization. This new level of scrutiny becomes a testimony of the recondite mysteries that biological systems still have to offer, so vividly illustrated in Albert Einstein’s words: “We still do not know one thousandth of one percent of what Nature has revealed to us.”