Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities
Open accessAbstract
IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
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Deletions and duplications of 16p11.2 have highly pleiotropic phenotypic effects, with strong links to ASD, ID, motor/developmental delay, dysmorphic features, and epilepsy/seizures.
“Deletions and duplications of 16p11.2 have highly pleiotropic phenotypic effects, with strong links to ASD [8–19], ID [8, 10, 12, 14–16, 19–21], motor/developmental delay [8–10, 12, 13, 15–19, 22], dysmorphic features [8, 12, 16, 17, 22], and epilepsy/seizures [10, 12, 17].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
16p11.2 deletions are associated with macrocephaly and obesity, while duplications often lead to microcephaly and low body weight/BMI.
“Deletions of 16p11.2 are associated with increased head circumference (macrocephaly) [10, 12, 17, 23] and obesity [10, 12, 16, 20], whereas duplications often result in below average head size (microcephaly) [10, 17, 23, 24] and low body weight/BMI [10, 24].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
Higher variability in FSIQ scores is observed among 16p11.2 duplication carriers than deletion carriers.
“Higher variability in FSIQ scores is observed among duplication carriers than deletion carriers [10, 19], suggesting a broader range of cognitive impairments in duplication patients.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
In studies with at least 50 subjects, 60-76% of 16p11.2 deletions were reported as de novo, while only 16-29% of 16p11.2 duplications occurred de novo.
“In studies with at least 50 subjects, between 60–76% of 16p11.2 deletions were reported as de novo events [10, 12, 34, 36], while only 16–29% of 16p11.2 duplications occurred de novo [10, 19, 34, 36].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
De novo and inherited 16p11.2 duplication carriers show no differences in most clinical outcomes and on cognitive tests.
“De novo and inherited duplication carriers also show no differences in most clinical outcomes [19], and on cognitive tests [10].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
Epilepsy/seizures ranks among the most common phenotypes observed in both 16p11.2 deletions and duplications.
“Epilepsy/seizures ranks among the most common phenotypes observed in both 16p11.2 deletions and duplications [10, 12, 16, 17, 33, 36] (Table 2).”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
A study of 270 duplication carriers and 442 deletion carriers found FSIQ significantly lower than intrafamilial controls in both duplication carriers (18.0 points) and deletion carriers (22.1 points).
“A study of 270 duplication carriers and 442 deletion carriers found that FSIQ was significantly lower than intrafamilial controls in both 16p11.2 duplication carriers (18.0 points) and deletion carriers (22.1 points) [10].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
16p11.2 duplication patients with ASD display more severe cognitive impairments than those without ASD.
“Interestingly, 16p11.2 duplication patients with ASD display more severe cognitive impairments than those without ASD [10], indicating that the severity of cognitive phenotypes may correlate with the pathogenesis of other neurodevelopmental disorders, particularly ASD.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
A very delayed (>24 months) age of first walking is observed in 6.1% of 16p11.2 deletion carriers and 15.9% of duplication carriers.
“A very delayed (>24 mo.) age of first walking is observed in 6.1% of deletion carriers and 15.9% of duplication carriers [10].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
BMI of 16p11.2 duplication patients is significantly lower than controls.
“Conversely, BMI of 16p11.2 duplication patients is significantly lower than controls [10, 24].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
Several reports indicate higher BMI in 16p11.2 deletion patients.
“Several reports indicate higher BMI in 16p11.2 deletion patients [10, 12, 23].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [10]
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- Authors
- D’Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L. G., Hippolyte, L., Hanson, E., Maillard, A. M., Faucett, W. A., Macé, A., Pain, A., Bernier, R., Chawner, S. J. R. A., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gérard, M., Goin-Kochel, R. P., Grant, E., Hunter, J. V., Isidor, B., Jacquette, A., Jønch, A. E., Keren, B., Lacombe, D., Le Caignec, C., Martin, C. L., Männik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M. J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J. A., Spence, S. J., Steinman, K. J., Tjernagel, J., Van Haelst, M., Shen, Y., Draganski, B., Sherr, E. H., Ledbetter, D. H., van den Bree, M. B. M., Beckmann, J. S., Spiro, J. E., Reymond, A., Jacquemont, S., Chung, W. K., & for the Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, T. 1. 2. E. C.
- Affiliations
- Columbia University (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Clinical Research Associates (US)
- Boston Children's Hospital (US)
- Geisinger Medical Center (US)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Washington (US)
- Cardiff University (GB)
- Inserm (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Seattle Children's Research Institute (US)
- Département de Génétique, Hôpital Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France 14INSERM U1163, Hôpital Necker–Enfants Malades, Paris, France15Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris,
- Ente Ospedaliero Ospedali Galliera (IT)
- Assistance Publique – Hôpitaux de Paris (FR)
- Section of Psychology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
- Baylor College of Medicine (US)
- Service de Génétique Médicale, Faculté de Médecine, Centre Hospitalier Universitaire (CHU) Nantes, Institut National de la Santé et de la Recherche Medicale (INSERM) Unités Mixtes de Recherche 957, Nantes, France
- Autism & Developmental Medicine Institute (US)
- University of Tartu (EE)
- University of California, San Francisco (US)
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France32Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
- PerkinElmer (United States) (US)
- Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales
- Simons Foundation (US)
- University of Lausanne (CH)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Chung, Wendy K.
- ORCID
- D’Angelo, Debra
- Lebon, Sébastien
- Chen, Qixuan
- Snyder, LeeAnne Green
- Hanson, Ellen
- Maillard, Anne M.
- Faucett, W. Andrew
- Macé, Aurélien
- Bernier, Raphael
- Chawner, Samuel J. R. A.
- Aylward, Elizabeth
- Conus, Philippe
- Forzano, Francesca
- Gérard, Marion
- Hunter, Jill V.
- Isidor, Bertrand
- Jacquette, Aurélia
- Jønch, Aia E.
- Keren, Boris
- Lacombe, Didier
- Metspalu, Andres
- Mignot, Cyril
- Mukherjee, Pratik
- Owen, Michael J.
- Rosenfeld, Jill A.
- Spence, Sarah J.
- Steinman, Kyle J.
- Shen, Yiping
- Draganski, Bogdan
- Sherr, Elliott H.
- Ledbetter, David H.
- Beckmann, Jacques S.
- Spiro, John E.
- Reymond, Alexandre
- Jacquemont, Sébastien
- Chung, Wendy K.
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2016-01-01
- Volume
- 73
- Issue
- 1
- Pages
- 20
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5894477
- OpenAlex
- W2188836807
- Cited by
- 277
- References
- 26
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 34 · 2023: 20 · 2022: 22 · 2021: 27 · 2020: 32 · 2019: 36 · 2018: 52 · 2017: 15 · 2016: 11 · 2015: 1
- FWCI
- 17.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- European Commission (604102)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (133044)
- Eesti Teadusagentuur (IUT20-60)
- Medical Research Council (MR/L010305/1)
- National Institute of Neurological Disorders and Stroke (R01NS058721)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- 16p11.2 duplication, 16p11.2 deletion, copy number variation, autism spectrum disorder, schizophrenia, intellectual disability, Full Scale IQ, verbal IQ, nonverbal intelligence, body mass index, head circumference, comorbidities, behavioral characteristics, anthropometric traits
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Adult, Autistic Disorder, Cerebellum, Child, Developmental Disabilities, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Cognition, Epilepsy, Female, Humans, Male, Intellectual Disability, Microcephaly, Middle Aged, Nervous System Malformations, Schizophrenia, Schizophrenic Psychology, Cohort Studies, Comorbidity, Case-Control Studies, Chromosome Disorders, Young Adult, DNA Copy Number Variations, Chromosome Duplication
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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