Diagnosing rare diseases is a long and difficult journey for patients and their families, but a recent study aims to improve this process. Here, we hear about its impact from both researcher and patient.
First , Andrew Giles, lead author of this work, discusses the impact of proactive exome reanalysis in advancing healthcare equity for rare disease patients. Then Jordan Hinrichs, mother of a rare disease patient who benefited from this research initiative, shares her family's story.
How do you define proactive exome reanalysis, and how does it differ from traditional one-time genomic testing?
Exome and genome tests typically provide diagnostic information at a single point in time. However, through reanalysis, previous results can be revisited and reinterpreted in light of new scientific discoveries, sometimes leading to additional insights or a revised diagnosis. Although reanalysis can significantly increase diagnostic yield, it is not routinely available to all patients; many laboratories only offer a one-time reanalysis or do not provide the service at all.
Proactive reanalysis differs in that our team of scientists continually monitors newly identified gene–disease relationships and compares these findings against cases in our database. When a relevant new association is found, we update the clinical report automatically – without requiring a clinician to request reanalysis and at no additional cost to the patient.
What does this new study add to the growing field of exome reanalysis?
Our laboratory has been performing exome reanalysis for more than 10 years. We do this because more than 100 new gene–disease associations are described each year, which might be relevant to patients with undiagnosed rare diseases.
The study published in Genetics in Medicine is notable because reanalysis rates had not previously been evaluated in the context of patient race or ethnicity.
How did reanalysis affect the number of positive exome results in your cohort
2,231 exomes were initially positive, and 2,657 were positive after all reanalysis events. This increased the overall diagnostic yield from 21 percent to 25 percent, meaning that 4 percent of originally negative cases became positive on reanalysis. More than 400 patients would have remained undiagnosed had reanalysis not been performed. Given the pace and volume of new scientific discoveries, many ordering providers may not have the information needed to know when a reanalysis should be requested.
How can pathologists, genetic counselors, and clinical teams work together to ensure equitable access to reanalysis and consistent interpretation of results?
One approach is to partner with laboratories that are committed to proactive, lifelong reanalysis of patient data. This helps ensure that all patients – regardless of race or ethnicity – benefit from new scientific discoveries as soon as they become available.
What are the barriers to wider adoption of exome reanalysis in clinical laboratories, and how might they be addressed?
Exome reanalysis is time- and cost-intensive, and the medical literature changes constantly. Clinicians see many patients each day and cannot realistically keep up with every newly identified gene–disease relationship for all previous cases. This is why it is essential for laboratories to take responsibility for proactive reanalysis rather than relying on clinicians to request it. Such an approach ensures that patients receive updated answers as soon as they become available and, as our research shows, helps reduce racial and ethnic disparities in access to diagnoses.
Jordan Hinrichs is mother of seven year-old Jerrick, who received a diagnosis through this initiative.
What was your family’s experience in trying to find a diagnosis for Jerrick?
We spent nearly five years searching for an explanation for our son’s many medical symptoms. The process often felt endless, overwhelming, and frustrating.
During my third trimester with Jerrick, we learned he had a heart defect. After he was born, we noticed several anatomical differences, and by age two he had been diagnosed with numerous conditions: Caudal Regression Syndrome with a tethered spinal cord, hypospadias, neurogenic bladder, incontinence, Heterotaxy Syndrome with bilateral lungs and a narrow airway, dextrocardia, motor delays, low muscle tone in his lower limbs, and bilateral vertical talus.
From infancy onward, we sought answers and consulted many clinicians. We had no family history of rare disease, and early genetic testing was negative. In February 2020, shortly before his third birthday, we proceeded with exome sequencing to look for a causative mutation. When that test also came back negative, it was devastating.
A year and a half later, we received an unexpected call from the genetic counseling team at Minnesota Children’s Hospital. Jerrick’s exome had been reanalyzed through the Patient for Life program after a new medical study identified variants in the ZMYM2 gene – present in Jerrick’s original exome – as a cause of genetic abnormalities. This updated interpretation finally provided a diagnosis: ZMYM2-related syndrome, the underlying genetic explanation for his medical challenges.
Can you describe what it meant to finally receive a diagnosis after reanalysis?
It was initially frightening to learn that Jerrick had a rare disease I knew nothing about. But once I had time to process the information, I felt relief and validation – we finally understood the root cause of the many conditions that had previously been treated as unrelated.
The diagnosis also helped my husband and me move past fears about what might have caused Jerrick’s symptoms and instead feel empowered to learn more and take action. One of the most meaningful outcomes has been connecting with other families whose children share the same diagnosis. Through a Facebook community for ZMYM2 families, I’ve gained both emotional support and practical guidance on managing care.
We also met with geneticists to determine whether we were carriers of the ZMYM2 mutation and were relieved to learn that we were not.
Did the new information help your healthcare team better understand or treat your child’s condition?
Although there is no targeted treatment for Jerrick yet, the diagnosis has given his care team at Minnesota Children’s Hospital a clearer framework for monitoring his symptoms, comparing his presentation with other documented cases, and ordering additional testing when appropriate.
What message would you share with pathologists and laboratory professionals about the impact of their diagnostic work on families?
Every new piece of data you uncover has the potential to end a patient’s or family’s diagnostic odyssey and guide them toward more informed, effective medical care.
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