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ACMG Session Highlights Progress Made by CSER Projects

NASHVILLE, Tenn. (GenomeWeb News) – At the American College of Medical Genetics and Genomics annual meeting, representatives from six centers funded through the National Human Genome Research Institute's Clinical Sequencing Exploratory Research (CSER) grants described approaches they're taking to assess the implementation of whole-exome or -genome sequencing in the clinic.

Speaking during a scientific session here yesterday morning, investigators from Baylor College of Medicine, Brigham and Women's Hospital, the Dana-Farber Cancer Institute, the University of North Carolina at Chapel Hill, the University of Washington, and the Children's Hospital of Philadelphia discussed their experiences with CSER-funded programs.

For her part, the University of Pennsylvania's Barbara Berhardt described an informed consent analysis performed in conjunction with CHOP's pediatric sequencing project, PediSeq, which focuses on children with intellectual disability, sudden cardiac death and arrest, and other conditions.

Based on audiotaped informed consent interviews with affected children and their parents, the researchers looked at how well families understood the types of information that might be communicated to them after a genetic test and determined the type of results families were comfortable receiving.

For that study, researchers considered the discussions and questions that came up as parents — and, in some cases, affected children — deliberated over consent decisions related to clinical sequencing. They also surveyed the families to look at everything from their motivation for participating in whole-exome testing to their understanding of the approach and likelihood that it would provide diagnostic information.

Berhardt noted that some results were returned automatically for that study, particularly those related to genetic variants believed causative or contributing to the condition in question. But families were also given a choice about whether they wanted to know about incidental findings — an option that nearly 86 percent of families selected.

For Baylor College of Medicine's BASIC3 research study, incidental findings are more routinely returned, explained Christine Eng, senior director of the BCM Medical Genetics Laboratories and medical director of the center's whole genome laboratory.

That effort uses exome sequencing in childhood cancer care for pediatric patients diagnosed with solid tumors at Texas Children's Hospital in the hopes of finding genetic alterations that impact everything from disease surveillance to treatment decisions at relapse.

More than 80 percent of the 151 children deemed eligible for that program have been enrolled so far, Eng noted, along with 176 of their parents. An analysis of the sequence data has unearthed dominant, pathogenic mutations in 8 percent of sequenced childhood cancer cases, along with mutations that have been implicated in rare, recessive cancer syndromes.

Along with cancer-related mutations, Baylor's BASIC3 study has turned up incidental but clinically actionable mutations such as alterations associated with Long QT syndrome in a small but significant proportion of study participants.

Through Baylor's broader clinical exome sequencing program, investigators have had a molecular diagnostic rate of 25 percent for the first 2,500 patients sequenced. The proportion of diagnosed cases has generally been highest for cases involving neurological conditions — a pattern found in other clinical sequencing programs as well.

In the 145 cases that have been enrolled in the University of North Carolina NCGENES project, for example, whole-exome sequencing has tracked down probable or possible genetic causes around 40 percent of the time, the study's principal investigator James Evans noted during yesterday's session.

Sequencing has been especially promising for uncovering potential genetic causes for individuals with neuropathy or retinal disease, he added, but has proven more difficult to apply to some other conditions, including cancer.

Evans called sequencing a "powerful but blunt tool," which has proven promising in the research setting. But, he argued that good evidence-based guidelines, protocols, and mutation-phenotype frequencies are needed when taking sequencing into the clinic for diagnosing disease or screening healthy populations.

Meanwhile, Gail Jarvik presented information from the University of Washington's randomized trial of whole-exome sequencing for individuals with familial colorectal cancer or polyposis.

So far, investigators involved in that study have tracked down potentially pathogenic mutations in around one-quarter of patients whose treatment included sequencing, compared to 15 percent in those who got standard care.

Jarvik pointed out that individuals who did not receive information related to their colorectal cancer or polyposis risk appeared slightly more prone to inquire about incidental findings, though that pattern requires further exploration.

Michael Murray discussed efforts to educate primary care physicians and specialists about interpreting genetic findings and communicate such results to their patients, both in the context of the MedSeq sequencing study being done at Brigham and Women's Hospital and in other programs.

Murray, who is affiliated with Geisinger Health System, outlined a health system designed by Geisinger to provide physicians with point of care information when communicating sequencing results to patients.

Finally, Eli Van Allen, a medical oncologist and post-doctoral researcher in computational biology in Levi Garraway's Dana-Farber Cancer Institute lab, outlined the
expert committee approach that researchers have been using to analyze and interpret whole-exome sequences from individuals with metastatic lung or colon cancer who have been assessed through the UO1 sequencing project at Dana-Farber.

Due to the massive amounts of data they've encountered so far, members of that team have come up with software known as "precision heuristics for interpreting the alteration landscape," or PHIAL, for interpreting alterations that may be important to clinical care for the cancer patients in question.

Van Allen noted that the group is using a similar algorithmic approach to understand genetic patterns in germline and to compare profiles in germline and somatic samples.