6. After a negative exome
Clinicians with complex patients Planned episode, genetics in practice. Pitsava 2025 found a molecular diagnosis in 54 of 353 undiagnosed families on genome sequencing, more than half in regions earlier testing had not assessed.
Listener title: After a negative exome: reanalysis, re-testing and what to say
Listener description: A laboratory director or clinical geneticist explains what can follow an exome that came back without a diagnosis: when to ask for reanalysis, when to order a new test, and how to explain a "negative" result to a patient. The episode also covers how to think through the cost of each option with a cash-pay patient. For clinicians caring for patients who remain undiagnosed after genetic testing.
Run of show (about 40 minutes)
| Time | Segment | What happens |
|---|---|---|
| 0:00 to 2:00 | Opening | The host introduces the topic and the guest's role. The guest discloses any industry relationships. The host notes that no patient information is discussed and that the guest speaks for themselves, not for the network. The host reads the starting point from the show notes: Pitsava 2025 found a molecular diagnosis in 54 of 353 undiagnosed families on genome sequencing, more than half in regions earlier testing had not assessed. |
| 2:00 to 12:00 | Reanalysis or a new test | When does the guest ask for reanalysis of existing data, and when do they order a new test? The guest explains what they look at first in a non-diagnostic report, what they ask the original laboratory, and how they read the ACMG points-to-consider statement on reevaluation and reanalysis (Deignan 2019) and the 2022 systematic review of reanalysis (Dai 2022). What does the Pitsava finding mean for an adult whose exome is several years old? |
| 12:00 to 20:00 | Explaining a "negative" result | How does the guest explain a non-diagnostic result so the patient does not hear "ruled out" or "nothing is wrong"? Which words help, and which cause trouble later? What should the clinician write in the chart so the next clinician knows what was tested, what was not, and when? |
| 20:00 to 28:00 | Composite scenario, not a real patient | The host states that this is a composite scenario, not a real patient. An adult with a long multisystem history brings an exome report from several years ago that found no diagnosis and asks whether anything has changed. The host and guest walk through the first conversation: what to request from the original laboratory, what to ask about new symptoms or new family history since the test, and who decides between reanalysis and a new test. |
| 28:00 to 36:00 | What each option costs a cash-pay patient | Discussed as method, never as what anyone should charge. What drives the cost of a reanalysis compared with a new test? What should a written quote cover, for example samples from relatives if the laboratory asks for them, and whether later reanalysis is included? How does the guest lay out the choices so the patient can decide before anything is ordered? |
| 36:00 to 40:00 | Closing | One practical takeaway: before choosing between reanalysis and a new test, ask the original laboratory for its written reanalysis policy and what it needs from the ordering clinician to start one. To reach the network, email hello@coloradocarenetwork.com or visit coloradocarenetwork.com/join. To suggest an episode, send the question in two sentences to the same address; members can also post it in #podcast on Slack. |
Guest prep questions (sent to the guest a week ahead)
- When a non-diagnostic exome report reaches you, what do you look at first to decide between reanalysis and a new test?
- What does a laboratory need from the ordering clinician to start a reanalysis, and how does an updated report reach the clinician and the patient?
- What would you want primary care listeners to take from Pitsava 2025 about regions that earlier testing did not assess?
- What words do you use to explain a non-diagnostic result, and which do you avoid?
- How do you walk a cash-pay patient through the cost of reanalysis compared with a new test, as method rather than a figure?
Show notes
This episode takes up the patient whose exome came back without a diagnosis. The guest explains how they choose between reanalysis of existing data and a new test, with reference to the ACMG points-to-consider statement on reevaluation and reanalysis, a 2022 systematic review of reanalysis, and Pitsava 2025, which found a molecular diagnosis in 54 of 353 undiagnosed families on genome sequencing, more than half in regions earlier testing had not assessed. The conversation covers how to explain a non-diagnostic result and how to talk through the cost of each option with a cash-pay patient, as method rather than price. A composite scenario, not a real patient, frames the middle of the episode.
- Sources:
- Pitsava G, Hawley M, Auriga L, et al. Genome sequencing reveals the impact of pseudoexons in rare genetic disease. Genet Med. 2025;27(11):101574. doi:10.1016/j.gim.2025.101574
- Deignan JL, Chung WK, Kearney HM, et al. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21(6):1267-1270. doi:10.1038/s41436-019-0478-1
- Dai P, Honda A, Ewans L, et al. Recommendations for next generation sequencing data reanalysis of unsolved cases with suspected Mendelian disorders: a systematic review and meta-analysis. Genet Med. 2022;24(8):1618-1629. doi:10.1016/j.gim.2022.04.021
- No patient information is discussed on this episode.
All planned episodes. To be the guest for this episode, email hello@coloradocarenetwork.com with the episode number.