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Leukodystrophy Trial Aims to Establish Whole-Genome Sequencing as First-Tier Diagnostic


NEW YORK (GenomeWeb) – Collaborators from the Myelin Disorders Program at Children's Hospital Philadelphia and Illumina have launched a clinical trial to evaluate whole-genome sequencing as a first-tier diagnostic for children with suspected leukodystrophy. .

The goal of the trial is to improve the diagnostic rate for children suspected of having one of several leukodystrophies — a collection of rare, genetic diseases that affect the brain, spinal cord, and sometimes the peripheral nerves. There are around 30 known leukodystrophies, all of which impact the growth of the myelin sheath, or white matter, and tend to worsen throughout a patient's life.

Currently, just around half of patients suspected of having a leukodystrophy ever receive a definitive molecular diagnosis, Omar Sherbini, who is coordinating the study, said in an interview. And, getting to that diagnosis takes on average eight years and can rack up on average $8,000 worth of costs, regardless of whether a patient actually receives a diagnosis or not. As such, the trial will also involve a cost-effectiveness analysis.

The WGS trial follows a previous exome sequencing study led by Adeline Vanderver at Children's National Medical Center in Washington, DC. Vanderver and the Myelin Disorders Program have since moved to CHOP.

In the previous study, researchers sequenced the exomes of 71 patients who had unresolved white matter abnormalities and were able to boost the diagnostic rate from around 50 percent using standard diagnostics to about 70 percent with exome sequencing.

Sherbini said that for the WGS study, the researchers plan to recruit around 200 individuals early in the diagnostic process. The first MRI to show that a patient was suffering from a white matter abnormality must have been done within two months of the patient enrolling in the LeukoSeq trial. "The idea behind that is to evaluate whole-genome sequencing as a stand-alone test," and not after the patient has already gone through a diagnostic odyssey, Sherbini said.

Half the patients will receive WGS, while the other half will go through a standard diagnostic workup. If patients go through a standard workup and still do not have a diagnosis, they will then also be sequenced, Sherbini said. Illumina will provide sequencing at no cost in its CLIA-certified laboratory with an expected turnaround time of about two months from sample to report.

The researchers have identified a set of known mutations that cause specific forms of leukodystrophies as well as a set of mutations that result in phenotypes that can be mistaken for leukodystrophy, but are in fact a different disease. The researchers decided to move to WGS since the known mutations that can cause the disease are diverse and include microdeletions. In addition, for the patients who are not diagnosed even after sequencing, the researchers are able to follow up on any variants of unknown significance. "Even if patients don't get a diagnosis, it helps them put closure on things," Amy Pizzino, who will head the genetic counseling team for the trial, said in an interview.

Sherbini added that in cases where a pathogenic mutation that is responsible for the patient's disease is identified, that information would go into the report returned to the treating physician and would be included as part of the patient's electronic medical record. The remainder of the sequence data will be available for research. In addition, families have the option of receiving results from secondary findings, Pizzino said. The secondary findings list includes the genes suggested by the American College of Medical Genetics and Genomics as being medically relevant because they enable action to be taken to monitor or prevent a potential disorder. Pizzino said that based on a pilot study of 11 families, she expects that the "vast majority" of families will opt to receive secondary findings.

As part of the study families will receive genetic counseling before sequencing and when results are returned, Pizzino said. Pizzino or another team member will meet with the family and talk to them before testing is sent out and after sequencing is done. If families are not local to Philadelphia, they have the option of discussing results with their local provider and speaking with Pizzino over the phone. "So families have a couple of different avenues for discussing those results," she said.

When sequencing does provide a molecular diagnosis, patients' treatment may or may not be impacted. Sherbini said that currently there are not many targeted treatments available for leukodystrophy, but a number of trials will be coming online for specific leukodystrophy subtypes based on patients' genetics. In addition, he said, a molecular diagnosis can also guide symptomatic care or predict certain symptoms while a genetic diagnosis can enable the parents to make informed family planning decisions. And, "when the time comes to roll out more therapeutic trials, having that understanding on the molecular level will help in terms of identifying appropriate patients for trials," Sherbini said.

Pizzino said that a molecular diagnosis can also bring families peace of mind. "The impact of a diagnosis is the biggest when it comes to the emotional turmoil that a family goes through and not so much the treatment options," she said.