Pre- and Postnatal Testing
Many firms use aCGH for postnatal diagnostics. Almost all, like CombiMatrix, also employ FISH testing and full chromosome analysis as needed.
In 2010 the American College of Medical Genetics and American Pediatrics Association designated aCGH as a first-tier method for postnatal testing. aCGH provides 20% greater detection of abnormalities compared with standard karyotyping, according to Dan Forsche, senior vp of marketing.
aCGH is making inroads quickly into prenatal testing as well. A 4,000-subject study on this application is under way. Results will be reported early next year at the meeting of the Society of Material and Fetal Medicine. By then, Forsche predicts, aCGH will have earned first-tier status for prenatal testing as well.
Cancer screening via aCGH is still considered experimental, or basic research, but the possibilities are as exciting as with pre- and postnatal testing. CombiMatrix employs a 180K array for hematologic cancers, which according to Forsche “picks up things that FISH cannot detect.”
The company also uses a tumor array containing about 100 oncogene probes, which may be used on both fresh and preserved tissue. Eventually, researchers hope to provide prognosis and advice on potential treatments based on the results.
CombiMatrix is also looking into sequencing, which will become more significant as the price falls from the current $8,000 to $5,000. A number of companies and research groups engage in targeted sequencing, which examines regions of the genome identified as trouble spots by aCGH.
An article published in Neuron described an aCGH technique for detecting the CNVs that underlie autism spectrum disorder (ASD). The study, undertaken on 1,000 families with one autistic child and one unaffected sibling, was conducted by Michael Wigler, Ph.D., of Cold Spring Harbor in collaboration with a group from Columbia University.
Since molecular biology began to dominate the study of autism, experts believed that inheritable genetic mutations were the principal cause of ASD. In unveiling a unified theory of this disorder, Dr. Wigler demonstrated that these mutations accounted for only about 25% of ASD cases.
The remainder arise from de novo mutations that did not appear in either parent and must have arisen spontaneously. Dr. Wigler identified the minimum number of involved CNVs at between 250 and 300.
Commenting on his work, Dr. Wigler noted, “The causes of autism when fully fleshed out are likely to be very diverse, some of which may be treatable much more readily than others. However, the diversity of causes implies that an effective future treatment for one form of ASD may be specific only for a narrow subset of those affected.”
Applying sophisticated mathematical analysis tools to aCGH, researchers resolved genomic irregularities—differences between affected and unaffected siblings—at much greater resolution than previously.
De novo CNVs were found in about 8% of children with ASD, compared with just 2% of unaffected siblings. The study design was biased toward discovering de novo CNVs, as ASD is very likely to be inherited in families with multiple affected children.
If Dr. Wigler's theory holds, more than half of all ASD cases arise from rare, de novo CNVs. Most of these CNVs, in fact, were observed only once. An accompanying paper identified the locations of these CNVs as regions of the genome previously implicated in studies of autism and cognitive disability.
Interestingly, girls were more likely to have a higher frequency of mutations than boys (11.7% vs. 7.4%), with more mutations involved (15.5 vs. 2.0), which would imply a higher incidence of ASD in females than males. Dr. Wigler hypothesized that females are somehow resistant to this phenotype, and that much larger genetic defects are required to confer the disease on girls than boys.
aCGH is showing promise in preconception testing as well. In 2010 physicians employed the technique to screen human eggs for genetic defects that increase the risk of miscarriage. As a result, two healthy babies were delivered in Germany, and one in Italy, of mothers who had experienced difficulty conceiving artificially and had a history of miscarriage. Several other post-aCGH pregnancies are currently under study, and a large-scale clinical trial is scheduled for 2012.
One might ask how an analytical technique can scan the entire genome and still provide a viable egg. Before an egg is fertilized it releases half of its 46 chromosomes to make room for the 23 that the sperm will provide. These chromosomes, held within a structure known as a “polar body,” are exact duplicates of those remaining in the egg. aCGH analyzes these castoff genes.
The technique has several advantages over conventional prenatal testing. It does not involve the egg itself, either before or after fertilization, nor does it touch the embryo, thereby nearly eliminating ethical or religious objections. And since it selects an egg deemed viable, the temptation to implant multiple embryos, as is commonly done today during in vitro fertilization, is lessened.