This story was first published May 14.
The International Standard Cytogenomic Array Consortium last week said that chromosomal microarrays should replace G-banded karyotypes as the first-tier technology to test individuals with unexplained developmental delay and intellectual disability, autism spectrum disorders, or multiple congenital anomalies.
The consortium backed up its new recommendation by saying chromosomal microarrays have a higher diagnostic yield than the current first-tier tech, G-banded karyotypes, and are technically superior to other cytogenetic testing methods.
At the same time, ISCA notes that arrays still cannot detect balanced translocations, and recommends that G-banded karyotype analysis should be reserved for patients "with obvious chromosomal syndromes," like Down syndrome, a family history of chromosomal rearrangement, or a history of multiple miscarriages.
The ISCA's recommendations appear in a review in the American Journal of Human Genetics.
"CMA gives us a huge improvement in the diagnostic yield of genetic testing and in our ability to counsel parents about why their child has developmental disability or multiple congenital anomalies," paper co-author and ISCA Director David Ledbetter said in a statement.
Ledbetter, who is director of the division of medical genetics at Emory University School of Medicine, has led ISCA since it was established in 2007 to bring together a group of clinical genetics laboratories and genomics experts focused on standardizing the collection of cytogenetic data.
According to Ledbetter, the AJHG paper should "help set the new standard of care for genetic evaluation of children with unexplained developmental delays and other birth defects, and should be a major step forward in using modern genomic technology in a clinical setting."
He told BioArray News last week that ISCA published the paper because there is "no official guideline or best practices statement yet from any of the relevant professional societies," mostly due to slow internal decision-making processes within those societies, which he did not name.
ISCA also wanted to reach clinicians that are using arrays together with karyotyping or those who are still using karyotyping with their recommendation. "There are many physicians still doing karyotype first, then array, and this greatly increases total costs of diagnostic testing," Ledbetter said. "We hoped to convince those remaining physicians they don’t need to do karyotype any more."
As discussed in the paper, ISCA recently conducted a literature review of 33 studies, including 21,698 patients tested by chromosomal microarrays. In the paper, ISCA provides an evidence-based summary of clinical cytogenetic testing comparing chromosomal microarray to G-banded karyotyping with respect to "technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation."
The authors found that for genetic testing of individuals with unexplained developmental delay and intellectual disability, autism spectrum disorders, or multiple congenital anomalies, chromosomal microarray offers a "much higher diagnostic yield" of 15 percent to 20 percent than a G-banded karyotype, which typically provides an explanation in about 3 percent of cases, excluding Down syndrome and other recognizable chromosomal syndromes, primarily because of its higher sensitivity for submicroscopic deletions and duplications.
According to the authors, arrays still cannot detect truly balanced rearrangements and low-level mosaicism, but these are "relatively infrequent causes of abnormal phenotypes in this population," affecting less than 1 percent of cases.
"Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA," the authors concluded. "G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes [like Down syndrome], a family history of chromosomal rearrangement, or a history of multiple miscarriages."
David Miller, a geneticist at Children's Hospital Boston and first author on the paper, said in the statement that using karyotypes to scan for chromosome problems has been a "well-accepted standard of care" for years. However, a chromosomal microarray is a "more powerful chromosome scan, so we believe it makes even more sense to do a CMA test in the majority of patients."
By positioning chromosomal microarrays as a first-tier test in most cases, ISCA is relegating G-banded karyotyping to second-tier usage. The technique has been used to help diagnose patients with chromosomal abnormalities since the early 1970s.
Replacing G-banding as the standard of care, though, will require more than papers; as the authors describe in their study, G-banding is a "widely accepted and uniform technique" with an "international system of cytogenetic nomenclature."
Ledbetter said that while adoption of arrays in cytogenetics continues to increase, the number of physicians still ordering karyotype is "significant." Additionally, chromosomal microarray is "more diverse in terms of techniques used, coverage, and approach to data interpretation," factors that may hinder its adoption.
Overcoming this lack of uniformity is the ISCA's raison d'être. In the paper, the consortium proposes a standard clinical algorithm to guide postnatal testing in this patient population, and advises that in clinical testing, traditional cytogenetic methods, such as fluorescence in situ hybridization, might offer the best confirmation for certain abnormal findings, though quantitative PCR and multiplex ligation and probe amplification have been used as well.
ISCA also provides guidelines on chromosomal array coverage probe density for both bacterial artificial chromosome- and oligonucleotide-based chips.
"The designs we recommend [in the AJHG paper] are pretty general and are consistent with most individual custom designs and manufacturer’s cytogenetics designs," Ledbetter said. "There is in fact remarkable consensus emerging on optimal designs." In February, British array vendor Oxford Gene Technology began selling catalog arrays based on ISCA's design (BAN 2/9/2010).
One of ISCA's efforts is the development of a chromosomal microarray database. Last year, Emory received a $3.5 million grant to develop a central public database of chromosomal microarray data from clinical labs (BAN 10/6/2009).The award is a National Institutes of Health Grand Opportunities grant under the American Recovery and Reinvestment Act of 2009 and is scheduled to end Aug. 31, 2011.
The database, housed at the National Center for Biotechnology Information at NIH, is expected to include approximately 200,000 patient samples over the next two years that will be used to develop standard guidelines for interpretation of chromosomal microarray tests, Emory said in a statement this week.
The database also will be used to develop additional summary recommendations and allow ISCA to work with vendors to make interpretation guidelines and software tools available to all clinical testing labs and to clinicians who want to better understand and interpret the laboratory data from their patients, it said.
There are currently over 100 clinical cytogenetics laboratories that will contribute genotype and phenotype data to the central database at NCBI, Emory said. In the paper, ISCA recommends that curated data be publicly released on a quarterly basis and made available to "major genomics resources and commercial vendors, as well as individuals and clinical laboratories."
An ISCA workshop scheduled for June in Bethesda, Md., will include clinicians, clinical labs, genomics and bioinformatics experts, as well as representatives from the top vendors developing chromosomal microarray technology and software for analysis.