Though recent studies have established chromosomal microarrays as a higher-yield tool for detecting constitutional abnormalities, geneticists continue to work to link copy number variations with specific phenotypes.
The US National Institute of Child Health and Human Development recently granted a team led by researchers from Columbia University Medical Center $5 million to better understand how variants uncovered by array analysis might be linked to developmental delay, structural abnormalities, and diseases.
"Our goal is to better define the genotype-phenotype relationship to offer patients better prognostic information," Ronald Wapner, director of maternal fetal medicine at CUMC and the study's principal investigator, told BioArray News this week.
CUMC also led a previous effort that determined that microarrays offer more clinically relevant information than conventional karyotyping, yielding the recommendation that arrays replace conventional karyotyping as a first-tier test in prenatal cases.
The results of that study, which involved 4,400 samples from 29 different centers, appeared last year in the New England Journal of Medicine (BAN 12/11/2012). Wapner discussed the team's plans for a follow on study with BioArray News in April 2012 (4/3/2012).
As part of the new study, set to run through 2017, Wapner said that the data featured in the NEJM article will be supplemented by 10,000 more cases recruited from 10 major prenatal diagnostic centers. Of those 10,000 cases, the researchers aim to follow between 300 and 600 children born with uncharacterized genetic variations for at least three years.
For the more common copy number variants associated with neurocognitive abnormalities, sibling controls will undergo similar evaluations to allow quantitative comparisons. The data from all participants will be included in a national registry of copy number variants and will be available for clinical and research use.
"We hope to accomplish a number of things including decreasing the number of variants of uncertain significance and better defining the phenotypes of the presently recognized pathogenic variants, especially those with variable expressivity," said Wapner.
"Many of the variants described from post-natal studies have the potential of biased ascertainment since they are only identified because an abnormal phenotype is seen clinically," he added. "This has the potential to miss some cases with mild or non-existent phenotypes," he said. "By following cases identified in utero before a phenotype is identified we eliminate this bias."
Project participants have also created a website where trial data will be collected and shared with parents and clinicians. Called prenatalarray.org, the site enables parents undergoing testing to learn more about array technology and to network with each other, and allows clinicians to provide information on the impact of genetic variants.
A third arm of the effort will assess what resources and educational materials women undergoing prenatal microarray testing find most helpful, both prior to and following testing. Investigators at the University of Pennsylvania are pursuing that part of the study.
A 'real world' study
While the first phase of the NICHD-sponsored prenatal study relied on consensus microarray platforms – Agilent Technologies' SurePrint CGH and Affymetrix's SNP 6.0 arrays – this follow-on study will not have a consensus microarray platform or design, Wapner said.
"Arrays will be run at clinical labs as part of clinical care," he said. "We wanted to make this a real world study," he added, noting that centers now offer CMA as part of regular care.
NewYork-Presbyterian/Columbia is the primary recruitment center for the study. The other participating centers are: the Center for Fetal Medicine in Los Angeles; Northwestern University; Cedars-Sinai Medical Center; San Francisco Perinatal; Carnegie Hill Imaging; Montefiore Medical Center; Mount Sinai Medical Center; Lenox Hill; and North Shore LIJ.
Wendy Chung, an associate professor of pediatrics in medicine at CUMC, is supervising the evaluation of the children. The data are being housed at the George Washington University data center.
The researchers are also working with Cambridge, Mass.-based genetics software firm Cartagenia to better categorize the findings and relate them to phenotype.
Additionally, Wapner said that the NICHD-funded group is collaborating with researchers in the UK. That effort, called the Evaluation of Array Comparative Genomic Hybridization in Prenatal Diagnosis of Fetal Anomalies, or EACH, is currently underway and is led by investigators at Newcastle University, University College London, and John Crolla at Salisbury District Hospital.
"We have designed much of the data collection so that cases can be combined," said Wapner.
Though the project is expected to continue over the next four years, Wapner said that the team hopes to be able to share some new information within the next two years.
Prenatalarray.org, the web-based portal associated with the project, is already online. Danville, Pa.-based Geisinger Health System is designing and hosting the resource.
Andy Faucett, director of policy and education at Geisinger, told BioArray News this week that the same web-based system has already been made available for Simons VIP Connect, which is focused on individuals with a 16p11.2 deletion or duplication, as well as DuchenneConnect, which is targeted to individuals with Duchenne Muscular Dystrophy.
According to Faucett, the site enables secure two-way communication with patients. "This allows researchers to conduct surveys about patients' attitudes and opinions about testing; it can also help them to understand how the patients dealt with learning that their child has a genetic variance," he said.
Geisinger will work to develop an online community to provide educational materials, resources, and support for women considering or using prenatal array testing. The online community will also follow children diagnosed with a CNV by prenatal testing, Faucett said.
He said that the online community has two ways for families to connect with each other and share information.
"At registration, they can indicate if they would like to connect with other women. If they answer yes, after signing in, a limited description shows up. This includes screen name, age of child, city, state and diagnosis, or CNV," he said.
A registered member can search by diagnosis, location, or age and click on that entry, said Faucett. An email form will then pop up allowing the member to send an invitation to connect to that member. "This is sent without revealing any contact information," he said. "If the other member is interested, she can respond and then they are connected offline." The site has discussion forums that allow issues to be posted, he noted. Registered participants may refer questions to genetic counselors through the site.
Faucett also addressed concerns about parental anxiety related to sharing information.
"In my experience the parents seem to take everything as something to consider, but don't rush to conclusions," said Faucett. "These are parents who have chosen to raise a child with a known CNV and they tend to focus on helping each other and providing support," he said. "Parents are doing this on Facebook and appreciate a more private setting to connect."