Rare Disease: Finding Answers for Patients with Mysterious Conditions

For a disease to be considered “rare,” fewer than 200,000 people in the United States will be affected by it. Some rare genetic disorders can be very difficult to diagnose, and for parents of a child with a rare disease, one of the most anxious times is the period of waiting for a diagnosis. It can be a very lonely and isolated time. You know your child is sick but have no idea what is causing their disease and, perhaps of greatest concern, you have no idea what the long-term outcomes for your child might be.

Your journey with rare disease more often than not begins with what we in the medical field describe as a “diagnostic odyssey.” It requires multiple visits to different pediatric specialists, seeing your child put through different tests and then experiencing the frustration of a negative result, and perhaps a referral to a different specialist. Your child may be getting sicker during this time, and for some, the search for an answer can become all consuming. After all, without a diagnosis, how can you hope for a treatment or cure?

While most genetic diseases have no cure, many have treatments. Through new medical technologies like gene therapy, some may even have a cure. Diagnosis is essential to both the doctors and the family caring for the child. Until recently, the average time patients with rare disease could wait for a diagnosis was eight years, with medical costs often surpassing the $100,000 mark. My team in the Institute for Genomic Medicine (IGM) at Nationwide Children’s Hospital is committed to helping kids with rare disease by reducing the time it takes to receive a diagnosis to just days rather than years.

For a patient with a rare genetic disease, the cause of their condition usually lies somewhere within their genome. The genome is the complete set of genetic material, what we call DNA, that we inherit from our parents, one copy of the genome from our mother and the other from our father. Each copy of the genome is made up of over 3 billion DNA base pairs, or letters, and can be found in every cell that has a nucleus. It includes all of the genes that contain the information to build and maintain our body.

Sometimes during early development, a pathogenic change - or typo - in this code can occur and this can lead to development of disease. For rare genetic conditions a single change in one of those 3 billion letters is often all it takes to cause a disease. The challenge we face diagnostically is finding where the change has occurred. The traditional approach has been to sequence likely genes one at a time until the change in the DNA is found, a slow and laborious approach often taking months or years to reach a diagnosis.

To solve this challenge, the IGM Clinical Lab is now providing our geneticist with clinical tests called Exome Sequencing (ES). This test uses Next-Generation Sequencing, a cutting-edge DNA sequencing technology that allows us to sequence all genes in the genome simultaneously and return results in a few months.

This technology has continued to advance over the last decade to the point where we can now simultaneously sequence the entire genome in under two days, for as many as 50 patient samples at a time. The Genome Sequencing (GS) method generates a lot of data and my team focuses on the computational needs to analyze all the data that this technology produces. We have developed software that allows us to rapidly identify any genetic changes that would explain a given patient’s disease.

As part of the Rare Disease Genomics Program at Nationwide Children’s, I am fortunate to work with a group of talented scientists, genetic counselors and clinical geneticists to use this GS technology to help find answers for families with kids suffering from the rarest genetic diseases. More than 170 families have enrolled in our study, many of which have been on the diagnostic odyssey for years.

So far, we have been able to find answers for over 40% of these extremely difficult cases, giving families long awaited answers and giving our clinicians a diagnosis that allows them to better treat and care for these kids. Some of the conditions we have discovered are so rare that only a handful of other patients in the world have been described with the condition.

Over the past year, using new laboratory technology and software developed by my group, we have been conducting a research trial of rapid Genome Sequencing (rGS). Through rGS we can go from collecting a patient’s blood sample to genetic diagnosis in under a week. We continue to strive to push that turnaround time down to a matter of days. Our hope is that these advances in genomic medicine will put an end to the diagnostic odyssey for generations to come.

Click here to learn more about the makeup of rare disease and the journey to diagnosis.