Skip to main content
Premium Trial:

Request an Annual Quote

ISCA Consortium Partners with Sequencing Group to Develop Clinical-Grade Human Variation Database


By Justin Petrone

The International Standards for Cytogenomic Arrays Consortium will work with a group of clinical genetics laboratories that are implementing next-generation sequencing to develop a database of human genetic variation information, according to members of ISCA's steering committee.

Christa Lese Martin, senior laboratory director at Emory Genetics Laboratory, said that both ISCA and a group of labs that use sequencing are seeking National Institutes of Health funding to support the project. The grant opportunity, awarded through the National Human Genome Research Institute, is called "Genomic Resource Grants for Community Resource Projects." Rather than compete against sequencing labs for funding, ISCA and partner labs decided to apply for funding together.

Martin spoke to BioArray News last week at the American College of Medical Genetics' annual conference in Charlotte, NC.

"We have joined forces," Martin said. "Whether it is a copy number variant or a point mutation, it's all mutations," she said. "The ultimate goal is to have a clinical-grade database that has human variation curated to the level of the ACMG guidelines — pathogenic, benign, or where does it fall in terms of uncertainty — so as we go along we hope to learn more about mutations that are of uncertain significance [compared] to ones that we know are tolerated by populations and ones we know that are linked to disease," she said.

Specifically, the group aims to coordinate the submission of variant and phenotypic data into ClinVar, a universal centralized database hosted by the National Center for Biotechnology Information.

Martin is one of the principal investigators on the grant application, along with Heidi Rehm, an associate molecular geneticist at Harvard Partners Center for Genetics and Genomics, and Robert Nussbaum, chief of the division of medical genetics at the University of California, San Francisco.

Founded in 2007, ISCA consists of a group of clinical cytogenetics and molecular genetics laboratories "committed to improving quality of patient care related to clinical genetic testing" using array technology, according to its website. The group has also created its own database that contains whole-genome array data from a subset of the ISCA Consortium's clinical diagnostic laboratories. According to Martin, the ISCA database currently contains about 30,000 cases.

ISCA has had a number of achievements since its establishment. It arrived at a consensus design for arrays used in constitutional cytogenetics, a design that has informed the content of most arrays on the market to date. Both Oxford Gene Technology and BlueGnome, for instance, market arrays that include the ISCA name: OGT sells CytoSure ISCA arrays and BlueGnome sells CytoChip ISCA arrays. ISCA also published a consensus statement in 2010 recommending that chromosomal microarray analysis become the first-tier test for identifying genetic abnormalities in postnatal samples (BAN 5/18/2010)

ISCA first received funding through an ACMG grant and later was awarded about $3.5 million to develop a CNV atlas of human development. But that two-year grant, set to expire this coming August, was a one-time "Grand Opportunity" award made through the American Recovery and Reinvestment Act of 2009, and therefore cannot be renewed. That has left ISCA looking for future financial support for its activities.

David Ledbetter, chief scientific officer at Geisinger Health System, said that ISCA should be notified if it receives the new NIH funding by the time of its annual meeting, to be held in May in Bethesda, Md. That will also be the first time that ISCA will sit down with labs that offering sequencing-based services. This "sequencing group" includes Harvard's Rehm; Sherri Bale, managing director at Gaithersburg, Md.-based genetic testing firm GeneDx; Madhuri Hegde, a senior director at Emory Genetics Lab; and "other lab directors who are implementing next-gen sequencing in their clinical labs," said Ledbetter.

"That will be the first face-to-face meeting bringing the CNV community and the sequencing community together," said Ledbetter. "Everything else has been by phone calls and e-mail for planning the grant application, so that will be an important meeting."

ISCA is working on a number of related projects that involve data sharing and analysis. Martin said that ISCA is working with a number of larger laboratories to get them to submit their data. Should they agree to submit, Martin said the number of cases in the database could double in the next year.

"We would very much like the [labs] to put the raw data in as well as just the actual CNV calls," said Martin. "The purpose of that is for researchers to be able to use that raw data for discovery of novel CNVs or to try and develop new algorithms," she said. Using its original NIH funding, ISCA has worked with software developer Cartagenia to create a "bridge component" for labs that wish to upload their data to the database. Some array vendors have also added buttons to their software packages to enable users to submit their raw data "because I think that everybody now realizes the importance of having this large dataset," Martin said.

ISCA is also overseeing the curation of existing data in its database, to make it easier for users to refer to the data to inform their calls. She said that ISCA is relying on an NIH-developed program that allows intralaboratory curation of data. "It takes the laboratory data against the known pathogenic regions on the ISCA list and says, 'You have called this benign and it is really pathogenic,' and it provides the information back to the lab," she said.

The next level of curation is to work through all available data in the database to organize a list of clinically known genomic regions to make it easier to make calls, Martin said. That way users would be alerted that all the CNVs in a particular region are pathogenic but one may be benign or of uncertain clinical significance, she said.

Have topics you'd like to see covered in BioArray News? Contact the editor at jpetrone [at] genomeweb [.]com.

The Scan

Germline-Targeting HIV Vaccine Shows Promise in Phase I Trial

A National Institutes of Health-led team reports in Science that a broadly neutralizing antibody HIV vaccine induced bnAb precursors in 97 percent of those given the vaccine.

Study Uncovers Genetic Mutation in Childhood Glaucoma

A study in the Journal of Clinical Investigation ties a heterozygous missense variant in thrombospondin 1 to childhood glaucoma.

Gene Co-Expression Database for Humans, Model Organisms Gets Update

GeneFriends has been updated to include gene and transcript co-expression networks based on RNA-seq data from 46,475 human and 34,322 mouse samples, a new paper in Nucleic Acids Research says.

New Study Investigates Genomics of Fanconi Anemia Repair Pathway in Cancer

A Rockefeller University team reports in Nature that FA repair deficiency leads to structural variants that can contribute to genomic instability.