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Once strictly the domain of research labs, gene-sequencing tests increasingly are being used to help understand the genetic causes of rare disease, putting insurance companies in the position of deciding whether to pay the $5,000 to $17,000 for the tests. But, according to an article in Reuters Health, a number of insurers, including Blue Cross Blue Shield, have reacted by putting the brakes on reimbursement. Insurers are demanding proof that the results will lead to meaningful treatments among the estimated 2 million Americans with a serious, undiagnosed disease, still an unlikely prospect in the majority of cases.

Genetics experts say that sequencing more than doubles the chances that families get a diagnosis, and saves spending on multiple tests of single genes. Even if no treatment is found, the tests can also end hugely expensive medical odysseys as parents frantically search for the cause of their child’s furtive illness.  Until the reimbursement issue is resolved, some smaller diagnostics players will likely stay on the sidelines, leaving the field to early adopters of the technology such as Ambry Genetics and Bio-Reference Laboratories’ GeneDx. And families short on resources will be left scrambling for funding.

Howard Jacob was the first to use gene-sequencing tools to unravel the mystery of a rare disease in 2009, leading to a bone marrow transplant that saved a little boy named Nic Volker. Five years later, Jacob’s molecular genetics lab at the Medical College of Wisconsin has done more than three dozen whole genome sequences, a test that reads the more than 3 billion letters that make up the human genetic code. They have sequenced 400 whole exomes, tests that look only at the protein-making segments of DNA known as exons, which represent 2 percent of the genome but account for 85 percent of disease-causing mutations.

Baylor College of Medicine in Houston, Texas, has handled 3,500 exome-sequencing cases since it started offering the test in 2011. A study of its first 250 cases showed whole exome sequencing identified the disease-causing gene in 25 percent of cases. Since the findings were published last October, the rate has increased to 28 percent as the list of known mutations has grown, said Dr. Christine Eng, who directs Baylor’s Whole Genome Sequencing Laboratory. Eng said insurance companies initially paid for most of the tests, but as volume has increased, more claims are getting denied. “There are some companies that are saying out and out, we won’t cover this test.”

Dr. Allen Bale, director of the DNA Diagnostic Lab at Yale School of Medicine in Connecticut, has seen a 500 percent increase in orders for exome sequencing since 2011. The lab does about 750 whole exome tests a year, and there, too, reimbursement is becoming an issue.

Dr. Julie Kessel, who directs coverage policy for Cigna, said sequencing requests were scarcely noticed five years ago. Now, “they’re very, very much on the radar.” Cigna generally does not cover whole genome or whole exome sequencing unless there is a clear clinical reason.

At Aetna Inc, Dr. James Cross, vice president of national medical policy and operations, said sequencing has gotten ahead of the evidence. Traditionally the company has made coverage decisions based on the individual test and whether it affects patient outcomes, he said. “With sequencing, you’ve got a lot of information that we don’t have that kind of evidence around.”

Last August, one of the industry’s biggest players, Blue Cross Blue Shield, issued a report saying exome sequencing might pinpoint the genetic cause of disease in up to half of patients, but only a fraction of those will be able to use that as guidance because treatments don’t exist yet. Since then, Blues plans in Louisiana, North Carolina and Pennsylvania have deemed exome sequencing “investigational,” meaning not eligible for coverage.

Insurers say their objections stem from a lack of evidence that the tests can improve patient care. But, there are some celebrated examples that it can, such as Alexis Beery of California, whose genetic defect left him with health problems similar to cerebral palsy. Genome sequencing led to highly effective treatments to replace the missing neurotransmitters that were causing the symptoms.