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Dr. Tomi Pastinen Receives Grant To Better Understand Ehlers-Danlos Syndrome Using 3rd Generation Sequencing

STORIES

Dr. Tomi Pastinen Receives Grant To Better Understand Ehlers-Danlos Syndrome Using 3rd Generation Sequencing

Tomi Pastinen, MD, PhD
Director, Genomic Medicine Center; Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Professor of Cancer Biology, University of Kansas School of Medicine
Full Biography

Tomi Pastinen, MD, PhD, Genomic Medicine Center, was recently awarded a 2-year basic science grant for $200,000 from Ehlers-Danlos Society.

Dr. Pastinen (Principal Investigator) and Eric Rush, MD, Clinical Genetics (Co-Investigator) aim to understand Ehlers-Danlos syndrome in their project entitled, “Hidden Genome in hEDS Resolved by 3rd Generation Sequencing”.

Many people consider Ehlers-Danlos syndrome to be one condition. However, our current understanding is more of a family of disorders, each with their own genetic cause and unique features. Recent advances in genetic technology have allowed for the discovery of the causes for several rare types of EDS. Hypermobility types EDS (hEDS) is the most common form of EDS, and although updates to the diagnostic criteria in 2017 improved our ability to appropriately diagnosis hEDS, they are not perfect. It would be extraordinarily helpful for patients if we were able to understand more about the underlying cause(s). Earlier research trying to answer this question suggested that a gene known as TNXB may be responsible for some cases of hEDS and a different type of EDS known as classic-like EDS (clEDS). It is likely that this is true, but this has proven to be a difficult gene to understand and at best it represents a very small percentage of hEDS patients. Therefore, much remains to be learned about the causes of hEDS.

Previous research has used a method known as whole exome sequencing (WES) which analyzes only the parts of the human genome that code for protein products and has thus far not been successful in findings causes of hEDS. Current efforts to use whole genome sequencing (WGS) to investigate the cause of hEDS offer additional potential for gene discovery, but the technology itself has limitations.

“We propose asking the question of the cause of hEDS in diverse ways. First, given the nature of our clinic, we can recruit significant numbers of entire families of affected patients and compare to other unaffected relatives. This will increase the likelihood that helpful results will be obtained,” said Drs. Pastinen and Rush.” Second, we will use the existing infrastructure of the Genomic Answers for Kids program to evaluate for known genetic disorders which may look like hEDS but have different genetic causes. We have already found several such patients in this study but anticipate that there are more.”

Third, genomic research thus far has generally used next-generation sequencing (NGS) technology for “short read” WES and WGS. NGS produces many small pieces of DNA that are then aligned by computer so that the entire sequence can be analyzed. Because the individual pieces of DNA are so small, there are many areas of the human genome that NGS cannot accurately analyze. This study proposes using 3rd generation long-read WGS for patients with a clinical diagnosis of hEDS and no diagnosis found on standard short read WES. Having a longer length to each sequenced DNA strand is beneficial for analyzing areas that NGS is unable to accurately analyze. This includes certain types of spelling errors and larger changes to the structure of the DNA. Fourth, we will use a person’s individual sequence to compare to “normal” references to look for extra pieces of DNA. In conclusion, we feel that the expertise and novel approach that Children’s Mercy Kansas City brings to this project offers significant potential for discovering the causes of hEDS.