Penetrance for copy number variants associated with schizophrenia
Abstract
The discovery of 'high-risk' de novo copy number variants (CNVs) associated with neuropsychiatric disorders such as schizophrenia offers the opportunity to translate these findings into useful tools for clinical geneticists. However, this will require estimation of penetrance for these variants, which has not yet been properly considered. To facilitate this process, we estimated the penetrance of CNVs associated with schizophrenia, at 15q13.3, 1q21.1, 15q11.2, 17p12, 2p16.3, 16p13.1 and 16p11.2 with a novel Bayesian method applied to pooled data from published case-control studies. For these CNVs, penetrance for schizophrenia was between 2 and 7.4%, which contrasts with the much higher penetrance for schizophrenia of the 22q11.2 deletions found in velo-cardio-facial syndrome. The highest penetrance was for 15q13.3 deletion (6-9% in individual studies) and the lowest was for 15q11.2 (2%). CNVs confer much higher risk for schizophrenia than common variants, but their penetrance is substantially lower than Mendelian disorders or other syndromic conditions. Since these CNVs predispose to multiple disorders, including epilepsy, autism and intellectual impairment, penetrance estimates will also need to take into account diagnostic specificity, and their overall penetrance for any neuropsychiatric disorder is likely to be much higher. Thus, although CNVs are still far from being clinically useful or relevant to genetic counselling for specific disorders, their detection may hold an important clinical value in predicting negative developmental outcomes.
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Rare de novo CNV considered causal may have intermediate effects and variable penetrance, so they must interact with other factors.
“For example, although rare de novo CNV are considered causal mutations, it is clear that mutations may have intermediate effect sizes and variable penetrance, as mentioned above [36, 42] so such mutations must be interacting with other factors.”
From Genetics of autism spectrum disorders (2011) · cites this paper as [42]
Identical CNVs have been associated with autism and schizophrenia, notably 16p11 rearrangements.
“identical CNVs have been associated with autism and schizophrenia, notably 16p11 rearrangements”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [42]
Identical mutations may be associated with highly divergent phenotype.
“identical mutations may be associated with highly divergent phenotype”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [42]
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- Authors
- Vassos, E., Collier, D. A., Holden, S., Patch, C., Rujescu, D., St Clair, D., & Lewis, C. M.
- Affiliations
- King's College London (GB)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Vassos, E.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-06-29
- Volume
- 19
- Issue
- 17
- Pages
- 3477-3481
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2169292316
- Cited by
- 182
- References
- 40
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 4 · 2018: 36 · 2017: 8 · 2016: 8 · 2015: 13 · 2014: 19 · 2013: 12 · 2012: 21
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- copy number variation, schizophrenia, penetrance, de novo mutations, 1q21.1, 15q11.2, 16p11.2, Bayesian estimation, genetic counseling, neuropsychiatric disorders, epilepsy, autism spectrum disorder, intellectual disability
- MeSH terms
- Chromosome Deletion, Humans, Schizophrenia, Case-Control Studies, Gene Dosage, DNA Copy Number Variations
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