Estimates of penetrance for recurrent pathogenic copy-number variations
Open accessAbstract
PURPOSE: Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci. METHODS: We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications. RESULTS: Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions. CONCLUSION: This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.
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About 0.25% of controls (n=66,462) are found with the 15q11.2 BP1-BP2 microdeletion.
“a review of reported data from control cohorts (n = 66,462 subjects) summarized to date show that about 0.25% of controls are found with the 15q11.2 BP1–BP2 microdeletion [18,27,28,29,30,31].”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [28]
The Methods section (page unavailable) includes 15q11.2 deletions in an analysis of 22,246 controls, and the Results discuss their frequency in cases and controls. Our copy does not report a pooled cohort of 66,462 controls or establish the claimed 0.25% control frequency. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe penetrance for the 15q11.2 microdeletion is low compared to the 16p11.2 deletion with a penetrance estimated at 62.4%.
“The penetrance for the 15q11.2 microdeletion is low compared to other microdeletion syndromes such as the 16p11.2 deletion with a penetrance estimated at 62.4% [28].”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [28]
The Results report 10.4% penetrance for 15q11.2 deletions versus 62.4% for *distal* 16p11.2 deletions. The cited sentence omits “distal,” making the 62.4% estimate sound applicable to 16p11.2 deletions generally; the paper also distinguishes proximal deletions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe penetrance of the 15q11.2 BP1-BP2 microdeletion is an approximate two fold increase over the general population risk.
“The penetrance of the 15q11.2 BP1–BP2 microdeletion has also been estimated at 10.4% [28] or an approximate two fold increase over the general population risk but may be due to paucity of inheritance data.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [28]
The penetrance of the 15q11.2 BP1-BP2 microdeletion has been estimated at 10.4%.
“The penetrance of the 15q11.2 BP1–BP2 microdeletion has also been estimated at 10.4% [28] or an approximate two fold increase over the general population risk but may be due to paucity of inheritance data.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [28]
More than 200 15q11.2 deletion carriers have been reported in clinical series with mild, moderate and severe neurodevelopmental symptoms as well as malformations.
“More than 200 15q11.2 deletion carriers have been reported in clinical series with mild, moderate and severe neurodevelopmental symptoms as well as malformations leading authors to delineate a microdeletion syndrome with considerable phenotypic variability9 and incomplete penetrance.10”
From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [10]
The penetrance of any pediatric phenotype in 16p11.2 deletion carriers is estimated at 62.4%, compared with 11.2% in duplication carriers.
“One study estimates that the penetrance of any pediatric phenotype in deletion carriers is 62.4%, relative to only 11.2% in duplication carriers [37].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [37]
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- Authors
- Rosenfeld, J. A., Coe, B. P., Eichler, E. E., Cuckle, H., & Shaffer, L. G.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Shaffer, Lisa G.
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 15
- Issue
- 6
- Pages
- 478-481
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC3664238
- OpenAlex
- W2010458876
- Cited by
- 425
- References
- 21
- Citations by year
- 2026: 25 · 2025: 29 · 2024: 30 · 2023: 33 · 2022: 32 · 2021: 46 · 2020: 28 · 2019: 21 · 2018: 63 · 2017: 28 · 2016: 26 · 2015: 25 · 2014: 21 · 2013: 17
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- copy number variation, penetrance, 1q21.1 deletion, 16p11.2 deletion, 22q11.2 duplication, congenital malformations, intellectual disability, developmental delay, prenatal diagnosis, genetic counseling, recurrence risk, Bayesian estimation
- MeSH terms
- Algorithms, Bayes Theorem, Genotype, Humans, Models, Genetic, Case-Control Studies, Penetrance, Genetic Predisposition to Disease, Genetic Loci, DNA Copy Number Variations
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