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How a pediatric hospital’s rare disease sequencing system is unlocking the whole genome

The Children’s Mercy Kansas City Research Institute announced on Monday that it is building what it calls the “most advanced genomic sequencing system in the world.” 

This claim refers to the work Children’s Mercy is doing through its Genomic Answers for Kids (GA4K) program. The health system rolled out the program three years ago with the goal of collecting genomic data and health information for 30,000 children and their families — it expects to create a database of at least 100,000 genomes over seven years. GA4K is already enjoying a significant milestone: providing 1,000 children with rare disease diagnoses based on its genome sequencing.

The program is unique because it uses 5-base genomic sequencing. This is a novel technology that combines multiple genomic technologies that have been used before into a single test, Dr. Tomi Pastinen, the director of Children’s Mercy Kansas City’s genomic medicine center, said in an interview.

“What 5-base genomic sequencing allows us to immediately do in the clinical space is replace multiple, usually successive genetic tests that are carried out on a patient into a single combined test and speeds up the analysis of multiple different types of genetic diseases,” he said.

Beyond the ability to diagnose all types of genetic diseases, 5-base genomic sequencing opens up our ability to “read the genome beyond the currently interpreted clinical genome,” Dr. Pastinen added. 

Genomic sequencing tests currently interpret only the protein coding part of the genome, which Dr. Pastinen claimed makes up only about 2% of the human genome. The use of 5-base genomic sequencing unveils the 98% of the genome that is currently not clinically analyzed. This is important because 60% cases involving children in which physicians suspect genetic disease remain unsolved with current genetic testing methods, Dr. Pastinen said.

On average, about 30-40% of pediatric rare disease cases receive a diagnosis, according to Dr. Pastinen. He said 5-base sequencing can help that percentage inch closer to half.

Dr. Pastinen claimed that the database being built for GA4K is the first of its kind for a couple reasons. The first is its scale, and the second is its comprehensiveness. While there have been pediatric rare disease studies that focus on specific indications, this program collects data from as many pediatric patients as possible who have been evaluated for an unsolved disease, Dr. Pastinen said.

This data comes from Children’s Mercy patients, as well as patients at the 17 partner institutions that take part in GA4K, two of which include NYU Langone Health and the University of Nebraska Medical Center, Dr. Pastinen said. These partners send their patients’ genomic samples for testing at Children’s Mercy.

“The program is unique because of the depth of data per patient — and because it’s dynamic,” Dr. Pasinen said. “And what that means is that we actually query the genome over the lifetime of the patient. The patient and their medical record lives with us. If there are changes in the medical record or changes in our understanding of the genome, we update the analysis in real time and actually share the data in real time with the scientific community and physician scientists.”

The 5-base sequencing used in GA4K expands upon previous work conducted by pediatric hospitals to better understand rare diseases in children. For example, San Diego-based Rady Children’s Institute for Genomic Medicine has also been a pioneer in the space, with a strong precision medicine program that deploys rapid genomic sequencing to quickly and accurately diagnose patients as early as possible. This program was championed by Dr. Stephen Kingsmore, who served as director of Children’s Mercy’s center for pediatric genomic medicine from 2011-2015.

Photo: Andy, Getty Images

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