Children's Mercy Kansas City unveils genomic sequencing system to identify rare diseases

The Children's Mercy Kansas City Research Institute unveiled what it calls the world's most advanced genomic sequencing system to more quickly diagnose rare pediatric diseases.

With the organization's 5-base HiFi genomic sequencing method, researchers are now able to simultaneously sequence the complete genome and methylome while extracting its functions to analyze disease variations in one test. The advancement will allow for faster and more accurate diagnoses for children, especially those with complex or rare diseases that can wait on average seven years for the correct diagnosis. The method was developed as a part of the hospital’s program, Genomic Answers for Kids, which launched in July 2019.

“So we are three years in this program which aims to achieve two major missions in advancing genomic medicine for sick children: One is to advance access, so testing at no cost to patients in order to capture all the undiagnosed cases in the Greater Kansas City area,” said Tomi Pastinen, M.D., director of the Genomic Medicine Center at Children's Mercy Kansas City, in an interview. “And the second feature of Genomic Answers for Kids is advancing the technologies to diagnose more of the children that have rare diseases, because only a minority of rare disease cases in children are solved today by clinical genomic medicine test, about 30% are solved and 70% remain unsolved.”

Pastinen hopes to increase the rate of diagnosis from under one-third to half of undiagnosed cases with the new tool. GA4K was built with $18.5 million in philanthropic funding. GA4K aims to create a database of 100,000 genomes collected through the genomic data of 30,000 children.

The program has already provided 1,070 diagnoses to families in search of answers, making it the world’s largest genomic data resource by HiFi genomic sequencing to date, according to Pastinen. Within that group, Pastinen’s team successfully sequenced 300 genomes.

“Many of these research approaches have not previously been integrated into clinical care of rare disease or clinical diagnostics of rare disease,” Pastinen said. “So I saw a pristine opportunity here to try to bring in some basic genomic advances into the translational space and do it in a meaningful manner in terms of helping families that are seeking answers for their child's illness.”

One-quarter of people with rare diseases wait between 15 months and 28 years between the onset of symptoms and diagnosis, according to a study on rare diseases by the U.S. Government Accountability Office. Four out of ten patients reported an initial misdiagnosis.

Most of the 7,000 to 10,000 known rare diseases disproportionately affect children, adolescents or young adults, according to the National Institute of Health. Pastinen says that only about 3,000 of these diseases are known well. He hopes that with a new library of genomic information that number and subsequent understanding can expand to help children outside the geographical scope of Children’s Mercy.

Due to the fact that families are not charged for the service, GA4K’s ability to support families' travel to the center is limited. A small number of patients, about 7%, travel from outside Children’s Mercy’s catchment area. By pairing with other institutions, GA4K plans to outsource the diagnosis of more patients who otherwise might wait years for the correct diagnosis and care.

“We have been engaging with other rare disease programs with the University of Nebraska Medical Center, as well as in NYU Langone Health, where we're providing these advanced tools that are not clinically yet available to families that are remaining without answers from their own research programs,” Pastinen said. “So we're trying to build these strategic partnerships to help like-minded rare disease programs with tools that they may not yet have.”

With the use of controlled access mechanisms provided by the NIH, data is shared with other rare disease scientists and programs. By crowdsourcing knowledge, understanding of rare diseases and their markers can expand.

Collaboration is essential, Pastinen said, since one facility may only see a rare disease once in 10 years. To share information regarding symptom manifestation, genetic markers, mutations and mutation disease links means to exponentially decrease misdiagnosis.

Even if a diagnosis isn’t reached or the wrong diagnosis is reached, Pastinen wants this information too. He sees that data as also essential to deciphering patterns. As things stand, he doesn’t see cross-institution sharing in this way. “And that’s required because of the rarity of these individual diseases; it requires joining forces and sharing data in a different way than have been achieved in most cases before,” Pastinen said.