Recalculated CNV penetrance: what it does and does not change for counselling
- 1Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Abstract
Goh et al. recently reported that most recurrent copy number variants (CNVs) are far less penetrant for intellectual disability (ID) than previously estimated, and recommended that fourteen should no longer be reported. We show that the lower estimates arise mainly from assuming the population prevalence of ID alone, while case counts derive from broad diagnostic referral cohorts in which about half of individuals were referred for other indications. The proposed formula estimates a risk difference rather than penetrance, and cases and controls were selected, assayed and phenotyped differently. Restricting the outcome to ID also leaves the analysis unable to inform risk for autism, epilepsy, psychiatric, cardiac and other phenotypes. We recommend that families receive phenotype-specific absolute risks for carriers alongside background risks, and that reporting decisions be made locus by locus by guideline bodies, considering all relevant phenotypes. The recalculated estimates inform this debate but are not yet sufficient grounds for changing reporting practice.
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BibTeX
@misc{breen2026recalculated,
title = {{Recalculated CNV penetrance: what it does and does not change for counselling}},
author = {G. Breen and H. Cullen and H. Paland and E. Vassos and L. Kilarski and M. E. Hauberg and B. Chaumette and S. Papiol and D. Duffin and K. L. Musliner and W. J. Peyrot and E. C. Schulte and K. Tammimies and K. M. Kendall},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.26364866},
url = {https://www.medrxiv.org/content/10.64898/2026.10.06.26364866v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Recalculated CNV penetrance: what it does and does not change for counselling
AU - G. Breen
AU - H. Cullen
AU - H. Paland
AU - E. Vassos
AU - L. Kilarski
AU - M. E. Hauberg
AU - B. Chaumette
AU - S. Papiol
AU - D. Duffin
AU - K. L. Musliner
AU - W. J. Peyrot
AU - E. C. Schulte
AU - K. Tammimies
AU - K. M. Kendall
PY - 2026
DA - 2026/10/06
PB - medRxiv
DO - 10.64898/2026.10.06.26364866
UR - https://www.medrxiv.org/content/10.64898/2026.10.06.26364866v1
AB - Goh et al. recently reported that most recurrent copy number variants (CNVs) are far less penetrant for intellectual disability (ID) than previously estimated, and recommended that fourteen should no longer be reported. We show that the lower estimates arise mainly from assuming the population prevalence of ID alone, while case counts derive from broad diagnostic referral cohorts in which about half of individuals were referred for other indications. The proposed formula estimates a risk difference rather than penetrance, and cases and controls were selected, assayed and phenotyped differently. Restricting the outcome to ID also leaves the analysis unable to inform risk for autism, epilepsy, psychiatric, cardiac and other phenotypes. We recommend that families receive phenotype-specific absolute risks for carriers alongside background risks, and that reporting decisions be made locus by locus by guideline bodies, considering all relevant phenotypes. The recalculated estimates inform this debate but are not yet sufficient grounds for changing reporting practice.
ER -