Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Trio RNA sequencing in a cohort of medically complex children

We previously published about this research in a story titled “RNA Sequencing: Hope for Improved Rare Disease Diagnosis” which can be found here. The study was originally published in the research publication The American Journal of Human Genetics. You can read the full text of the study here. 

This research team was affiliated with The Hospital for Sick Children (SickKids).

What Happened?

Whole genome sequencing has been a benchmark for the diagnosis of rare genetic disorders. While this genetic test is highly effective, it still has some limitations, one of which is that genome sequencing isn’t able to determine which non-coding gene variants are causing a disease. Another approach, dubbed RNA sequencing, has begun to emerge as a method that can circumvent this problem, but it hasn’t been used or studied extensively.

In this study, researchers used a combination of genome sequencing (GS) and RNA sequencing (RNA-seq) with a trio design in order to diagnose 97 people from 39 families who experienced “unexplained medical complexity.” The trio approach involves not only the sequencing of the patient, but the patient’s parents as well. These subjects were part of SickKids’ Complex Care Program. Of the patients whose diagnosis could not be confirmed with GS, RNA-seq provided meaningful diagnostic info in 8% of cases. 

The researchers concluded that the use of RNA-seq alongside GS provided a clear advantage over utilizing GS alone for diagnosis. The trio design made the analysis more efficient and allowed the scientists to finish the review of the test results more quickly. The scientists also noted inherited RNA patterns within families, which could be a future avenue of research.

Why Does it Matter?

SickKids has been working on the RNA sequencing platform for six years, and the results of this study have validated its usefulness. While genome sequencing provides a picture of a person’s genetic code, RNA sequencing takes a look at how that code is being interpreted. While only 8% of patients were diagnosed because of RNA sequencing, this is still a very meaningful improvement over genome sequencing alone. The researchers see multiple avenues of future research using the approach:

“We hope that the results of our study will help support the inclusion of clinical based RNA-testing in diagnostic workflows for children with rare conditions.” – Dr. Gregory Costain and Dr. Jim Dowling, co-lead authors of the study

RNA sequencing is also playing a role in other programs at the hospital, such as in The Centre for Applied Genomics, part of the SickKids Research Institute. Future research will allow clinicians and scientists to gain a better grasp of when RNA sequencing can make an impact on a case-by-case basis. 

“We have built a strong bridge between the research and clinical labs at SickKids which will benefit ongoing and future studies contributing to precision medicine becoming standard of care, as well as patients throughout the hospital. By carefully sequencing and analyzing RNA from diverse populations of sick and healthy children, we have the potential to improve how we find diagnoses for patients with rare genetic conditions.” – Dr. Michael Wilson, Senior Scientist, Genetics & Genome Biology Program