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Cited by 331Genomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental DisordersAutism Spectrum Disorder Research

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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

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Zufferey, Flore, Sherr, Elliott H, Beckmann, Noam D, Hanson, Ellen, Maillard, Anne M, Hippolyte, Loyse, Macé, Aurélien, Ferrari, Carina, Kutalik, Zoltán, Andrieux, Joris, Aylward, Elizabeth, Barker, Mandy, Bernier, Raphael, Bouquillon, Sonia, Conus, Philippe, Delobel, Bruno, Faucett, W Andrew, Goin-Kochel, Robin P, Grant, Ellen, Harewood, Louise, Hunter, Jill V, Lebon, Sébastien, Ledbetter, David H, Martin, Christa Lese, Männik, Katrin, Martinet, Danielle, Mukherjee, Pratik, Ramocki, Melissa B, Spence, Sarah J, Steinman, Kyle J, Tjernagel, Jennifer, Spiro, John E, Reymond, Alexandre, Beckmann, Jacques S, Chung, Wendy K, Jacquemont, Sébastien, on behalf of the Simons VIP Consortium, on behalf of the 16p11.2 European Consortium·2012·Journal of Medical Genetics
DOI 10.1136/jmedgenet-2012-101203PMC PMC3494011
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Abstract

Background: The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

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Figures

Figure 1 The 16p11.2 locus. Highly homologous blocks of low copy repeats (LCRs) may act as substrates for non-allelic homologous recombination, predisposing to genomic disorders.48 Five LCRs have been defined as mediators of recurrent and clinically relevant imbalances within the 16p11.2 chromosomal band. To clarify the terminology, we propose to number these ‘recombination hotspots’ from telomere to centromere as breakpoints BP1 to BP5. The current study describes only features associated with the proximal 600 kb recurrent deletion, delineated by BP4 and BP5 at genome sequence coordinates 29.5 and 30.1 Mb, respectively. Distal BP2-BP3 and BP1-BP3 mediated rearrangements, of respectively 220 and 550 kb, containing the SH2B1 gene, have also been reported in individuals with early onset obesity and variable degrees of developmental delay.49 Several recurrent rearrangements overlap the proximal BP4-BP5 region studied here including the 1.7 Mb deletions and duplications from BP1 to BP59 which should be considered as distinct entities. (A) Rearrangements are schematically pinpointed with reddish bars while grey bars and striated blocks indicate intervals of recurrent polymorphisms reported in the Database of Genomic Variants (http://projects.tcag.ca/variation) and common sequence stretches, respectively. (B) Genes encompassed by the genomic region between BP4 and BP5 are shown. All genomic positions are given according to the human genome build hg18/NCBI 36.
Figure 1 The 16p11.2 locus. Highly homologous blocks of low copy repeats (LCRs) may act as substrates for non-allelic homologous recombination, predisposing to genomic disorders.48 Five LCRs have been defined as mediators of recurrent and clinically relevant imbalances within the 16p11.2 chromosomal band. To clarify the terminology, we propose to number these ‘recombination hotspots’ from telomere to centromere as breakpoints BP1 to BP5. The current study describes only features associated with the proximal 600 kb recurrent deletion, delineated by BP4 and BP5 at genome sequence coordinates 29.5 and 30.1 Mb, respectively. Distal BP2-BP3 and BP1-BP3 mediated rearrangements, of respectively 220 and 550 kb, containing the SH2B1 gene, have also been reported in individuals with early onset obesity and variable degrees of developmental delay.49 Several recurrent rearrangements overlap the proximal BP4-BP5 region studied here including the 1.7 Mb deletions and duplications from BP1 to BP59 which should be considered as distinct entities. (A) Rearrangements are schematically pinpointed with reddish bars while grey bars and striated blocks indicate intervals of recurrent polymorphisms reported in the Database of Genomic Variants (http://projects.tcag.ca/variation) and common sequence stretches, respectively. (B) Genes encompassed by the genomic region between BP4 and BP5 are shown. All genomic positions are given according to the human genome build hg18/NCBI 36.CC BY-NC · PubMed Central
Figure 2 Distribution of full scale intelligence quotient (FSIQ) and body mass index (BMI) in deletion carriers.(A) Distribution of FSIQ of 16p11.2 BP4-BP5 deletion carriers (grey bars), intrafamilial non-carrier relatives (control, blue bars) and general population (blue bell curve). The red dashed vertical line represents the FSIQ threshold (70) for intellectual disability (ID). FSIQ is on average 32 points lower in carriers (n=71; mean=76.1; SD=16.4) when compared to their relatives who did not carry the deletion (n=68; mean=108.3; SD=10.9). SD in carriers is similar to that of the reference population (mean=100; SD=15). Bin size was calculated to obtain 10 equal sized bins. (B) Cross-sectional distribution of BMI in carriers (circles: female; open squares: male). BMI progressively increases throughout childhood and adulthood. 70% of the adult carriers are obese (BMI ≥30). The dashed lines represent the 3rd and 97th Center for Disease Control and Prevention (CDC) centile, while the dotted lines pinpoint the thresholds for underweight (BMI=18.5), obesity (30), and morbid obesity (40).
Figure 2 Distribution of full scale intelligence quotient (FSIQ) and body mass index (BMI) in deletion carriers.(A) Distribution of FSIQ of 16p11.2 BP4-BP5 deletion carriers (grey bars), intrafamilial non-carrier relatives (control, blue bars) and general population (blue bell curve). The red dashed vertical line represents the FSIQ threshold (70) for intellectual disability (ID). FSIQ is on average 32 points lower in carriers (n=71; mean=76.1; SD=16.4) when compared to their relatives who did not carry the deletion (n=68; mean=108.3; SD=10.9). SD in carriers is similar to that of the reference population (mean=100; SD=15). Bin size was calculated to obtain 10 equal sized bins. (B) Cross-sectional distribution of BMI in carriers (circles: female; open squares: male). BMI progressively increases throughout childhood and adulthood. 70% of the adult carriers are obese (BMI ≥30). The dashed lines represent the 3rd and 97th Center for Disease Control and Prevention (CDC) centile, while the dotted lines pinpoint the thresholds for underweight (BMI=18.5), obesity (30), and morbid obesity (40).CC BY-NC · PubMed Central
Figure 3 Height, body mass index (BMI), and head circumference (HC) in 16p11.2 BP4-BP5 deletion carriers through development. Height (panel A), BMI (panel B) and HC (panel C) mean Z scores (and corresponding p values in red) for each age window were computed using a mixed effect model to analyse longitudinal and cross-sectional data together. p Values are derived from a two-sided t test of the fixed effects estimates probing whether they are significantly different from 0. Full red dots are p values surviving multiple testing correction (significance's threshold at 6.3×10−3 for height in both obese and non-obese, at 5.6×10−3 for BMI, and at 7.1×10−3 for HC) as opposed to empty red dots. Number of cases N is indicated for each age category. Panel A: Deletion carriers were classified in two groups; either the ‘obese group’ (squares) if they presented obesity at least once during their development, or the non-obese group (triangles). Height is significantly increased in prepubertal obese carriers while non-obese children remain slightly shorter than the general population. Panel B: BMI is significantly elevated by 3.5 years of age. Panel C: HC follows a rapid increase (+1.74 Z score, p=4.8×10−4) during infancy, and remains high throughout life. Panel D: Longitudinal measures of BMI in a subset of 12 carriers illustrating different age onsets of BMI acceleration. The grey area specifies the interval between the 3rd and 97th centile as defined by the WHO data (http://www.who.int/childgrowth/en) between 0–2 years and the Centre for Disease Control and Prevention data above 2 years of age. The white line marks the 50th centile. All available longitudinal data are included in supplementary figure S2.
Figure 3 Height, body mass index (BMI), and head circumference (HC) in 16p11.2 BP4-BP5 deletion carriers through development. Height (panel A), BMI (panel B) and HC (panel C) mean Z scores (and corresponding p values in red) for each age window were computed using a mixed effect model to analyse longitudinal and cross-sectional data together. p Values are derived from a two-sided t test of the fixed effects estimates probing whether they are significantly different from 0. Full red dots are p values surviving multiple testing correction (significance's threshold at 6.3×10−3 for height in both obese and non-obese, at 5.6×10−3 for BMI, and at 7.1×10−3 for HC) as opposed to empty red dots. Number of cases N is indicated for each age category. Panel A: Deletion carriers were classified in two groups; either the ‘obese group’ (squares) if they presented obesity at least once during their development, or the non-obese group (triangles). Height is significantly increased in prepubertal obese carriers while non-obese children remain slightly shorter than the general population. Panel B: BMI is significantly elevated by 3.5 years of age. Panel C: HC follows a rapid increase (+1.74 Z score, p=4.8×10−4) during infancy, and remains high throughout life. Panel D: Longitudinal measures of BMI in a subset of 12 carriers illustrating different age onsets of BMI acceleration. The grey area specifies the interval between the 3rd and 97th centile as defined by the WHO data (http://www.who.int/childgrowth/en) between 0–2 years and the Centre for Disease Control and Prevention data above 2 years of age. The white line marks the 50th centile. All available longitudinal data are included in supplementary figure S2.CC BY-NC · PubMed Central

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  1. Wechsler D . Wechsler adult intelligence scale—third edition. Administration and scoring manual San Antonio, TX: The Psychological Corporation, 1997. · DOI · Paper page
  2. Sparrow SS Cichetti DV Balla DA . Vineland adaptative behavior scales. 2nd edn. Livonia, MN: Pearson Assessments, 2006. · DOI

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Authors
Zufferey, F., Sherr, E. H., Beckmann, N. D., Hanson, E., Maillard, A. M., Hippolyte, L., Macé, A., Ferrari, C., Kutalik, Z., Andrieux, J., Aylward, E., Barker, M., Bernier, R., Bouquillon, S., Conus, P., Delobel, B., Faucett, W. A., Goin-Kochel, R. P., Grant, E., Harewood, L., Hunter, J. V., Lebon, S., Ledbetter, D. H., Martin, C. L., Männik, K., Martinet, D., Mukherjee, P., Ramocki, M. B., Spence, S. J., Steinman, K. J., Tjernagel, J., Spiro, J. E., Reymond, A., Beckmann, J. S., Chung, W. K., Jacquemont, S., on behalf of the Simons VIP Consortium, & on behalf of the 16p11.2 European Consortium
Affiliations
  • Centre Hospitalier Universitaire Vaudois (CH)
  • University of California, San Francisco (US)
  • Boston Children's Hospital (US)
  • SIB Swiss Institute of Bioinformatics (CH)
  • Centre Hospitalier Universitaire de Lille (FR)
  • Seattle Children's Research Institute (US)
  • University of Washington (US)
  • Groupe Hospitalier de l'Institut Catholique de Lille (FR)
  • Geisinger Medical Center (US)
  • Department of Pediatrics, Psychology Section, Baylor College of Medicine, Houston, Texas, USA
  • Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • University of Lausanne (CH)
  • Baylor College of Medicine (US)
  • Emory University (US)
  • Simons Foundation (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Chung, Wendy K
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2012-10
Volume
49
Issue
10
Pages
660-668
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmedgenet-2012-101203
PMC
PMC3494011
OpenAlex
W2117381227
Cited by
326
References
55
Citations by year
2026: 7 · 2025: 12 · 2024: 28 · 2023: 18 · 2022: 22 · 2021: 21 · 2020: 24 · 2019: 25 · 2018: 53 · 2017: 25 · 2016: 20 · 2015: 26 · 2014: 29 · 2013: 15
FWCI
13.27
Type
journal article
Language
en
Update notices
correction (2014-07-01)
Open access
Licence
cc-by-nc
Locations
  • Journal of Medical Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • IRIS (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
  • Use Siena air (University of Siena) (submittedVersion, cc-by-nc)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • BORIS (University Library Bern) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • National Science Foundation
  • Simons Foundation
  • Simons Foundation Autism Research Initiative
  • European Commission
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • Fondation Leenaards
  • Université de Lausanne
  • European Regional Development Fund
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052431)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
16p11.2 deletion syndrome, autism spectrum disorder, neuropsychiatric disorders, intellectual disability, obesity, seizures, head circumference, energy imbalance, neurodevelopmental disorders, rare variants, phenotypic characterization
MeSH terms
Adolescent, Adult, Child, Developmental Disabilities, Child Development Disorders, Pervasive, Chromosome Deletion, Chromosomes, Human, Pair 16, Female, Heterozygote, Humans, Intelligence Tests, Male, Phenotype, Syndrome, Body Mass Index, Gene Order, Young Adult

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