Arrhythmias & electrophysiology
Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes
Authors' conclusion
Variant reclassification led to changes in 23% of probands, both downgrading and upgrading status, even among probands initially thought to be pathogenic. When comparing later to earlier eras, VUS variants increased while diagnostic yield decreased.
Study context
- Population
- Probands <18 years undergoing genetic testing for suspected inherited cardiac conditions associated with arrhythmias, 2007 to 2018
- Participants
- 306 probands
- Exposure
- Early era vs later era; higher vs lower clinical disease likelihood
- Outcome
- Longitudinal changes in diagnostic yield and variant classification (reclassification in October 2023 using VarSome and ACMG criteria)
Methodological detailssingle-centre
- Single-centre
Main finding
As reported in the abstract
Diagnostic yield and variant classification
- Initial testing diagnostic
- 23.2%
- Initial testing non-diagnostic (33.7% no variant, 21.9% B/LB)
- 55.6%
- Initial testing variants of uncertain significance (VUS)
- 21.2%
- Diagnostic yield decreased, early vs later era
- 34.1%-15.3%
- VUS increased, early vs later era
- 9.3%-29.9%
- Non-diagnostic remained similar, early vs later era
- 55% to 57%
- Probands with ≥1 variant whose variants changed on reclassification (46/203)
- 22.7%
- Diagnostic variants downgraded to VUS or non-diagnostic (7/71)
- 9.9%
- VUS changed (23.1% upgraded, 36.9% downgraded)
- 60.0%
Observational data: associations, not effects.
Further findings
| Outcome | OR (95% CI) | P value | |
|---|---|---|---|
| Diagnostic result, higher vs lower clinical disease likelihood, regardless of era | 6.3 (3.2–12.4) | P < 0.0001 | |
| 0.050.21520Odds ratio (log scale) |
Original publication
Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes. Heart Rhythm. Published 16 May 2025. doi:10.
Summarised from the published abstract; every number is checked against it