Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15 q 11.2, Specifically Breakpoints 1 to 2
Open accessAbstract
The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants ( CNVs ). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 ( BP 1 and BP 2) have been reported cosegregating with autism spectrum disorder ( ASD ). Although evidence supporting an association between BP 1‐ BP 2 CNVs and autism accumulates, the magnitude of the effect of BP 1‐ BP 2 CNVs remains elusive, posing a great challenge to recurrence‐risk counseling. To gain further insight into their pathogenicity for ASD , we estimated the penetrance of the BP 1‐ BP 2 CNVs for ASD as well as their effects on ASD ‐related phenotypes in a well‐characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20 T :9 NT ). The penetrance of the BP 1‐ BP 2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD ‐related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP 1‐ BP 2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current A merican C ollege of M edical G enetics guidelines for interpretation of postnatal CNV , the BP 1‐ BP 2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance ( VOUS ): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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Chaste et al. found a greater effect on the autism phenotype in males.
“Chaste et al. [32] found a small risk regarding this microdeletion and autism but a greater effect on the autism phenotype in males and when maternally inherited.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [32]
The Discussion says SRS analyses suggested that males might be more sensitive to the CNV, with a greater effect in fathers than mothers. This was a tentative finding about autism-related social responsiveness in relatives, not an established greater effect on the autism phenotype generally; the same section reports no effect on phenotype severity in probands. (LLM, conf=0.87)
Experimental — accuracy not yet measuredChaste et al. found a greater effect on the autism phenotype when the microdeletion was maternally inherited.
“Chaste et al. [32] found a small risk regarding this microdeletion and autism but a greater effect on the autism phenotype in males and when maternally inherited.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [32]
The Results section (‘Effects of BP1-BP2 CNVs on autism related symptoms in relatives’; page unavailable) reports that maternally inherited CNVs had a greater effect on autism-related scores in unaffected siblings. But the analysis combined deletions and duplications, so it does not establish a greater effect for the microdeletion specifically. The Discussion calls the parent-of-origin finding exploratory and says larger samples are needed to confirm it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChaste et al. found a small or overall modest effect for the 15q11.2 BP1-BP2 microdeletion on autism in a sample of 2525 families with autism.
“They reported an overall modest effect for this copy number variant for autism in studying a sample of 2525 families with autism [32].”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [32]
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Cites
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · cited 6× · see citing works
“…are beginning to elucidate the complex architecture of autism risk, the contribution of inherited rare variation to genetic risk for autism remains elusive [Bucan et al., 2009; Girirajan, Johnson et al., 2013; Krumm et al., 2013; Morrow et al., 2008; Pinto et al., 2010; Sanders et al., 2011, 2012].”
BackgroundResultInfluentialSelf-citationStandardizing ADOS Scores for a Measure of Severity in Autism Spectrum Disorders
Gotham, K., Pickles, A., & Lord, C. (2009) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-008-0674-3 · Cited by 1,605 · see citing works
Self-citationPeabody Picture Vocabulary Test--Fourth Edition
Dunn, L. M., & Dunn, D. M. (2012) · PsycTESTS Dataset · doi:10.1037/t15144-000 · Cited by 914 · see citing works
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
de Kovel, C. G. F., Trucks, H., Helbig, I., Mefford, H. C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., et al. (2010) · Brain · doi:10.1093/brain/awp262 · Cited by 445 · see citing works
Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., Alvarez Retuerto, A. I., Imielinski, M., Hadley, D., Bradfield, J. P., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000536 · Cited by 424 · see citing works
Self-citationThe Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay
Kirov, G., Rees, E., Walters, J. T. R., Escott-Price, V., Georgieva, L., Richards, A. L., Chambert, K. D., Davies, G., Legge, S. E., Moran, J. L., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.022 · Cited by 368 · see citing works
A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
Zufferey, F., Sherr, E. H., Beckmann, N. D., Hanson, E., Maillard, A. M., Hippolyte, L., Macé, A., Ferrari, C., Kutalik, Z., Andrieux, J., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101203 · Cited by 326 · see citing works
Self-citationDoornbos, M., Sikkema-Raddatz, B., Ruijvenkamp, C. A. L., Dijkhuizen, T., Bijlsma, E. K., Gijsbers, A. C. J., Hilhorst-Hofstee, Y., Hordijk, R., Verbruggen, K. T., Kerstjens-Frederikse, W. S. (., et al. (2009) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2009.03.010 · Cited by 165 · see citing works
Sahoo, T., Bacino, C. A., German, J. R., Shaw, C. A., Bird, L. M., Kimonis, V., Anselm, I., Waisbren, S., Beaudet, A. L., & Peters, S. U. (2007) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201859 · Cited by 152 · see citing works
Self-citationTransmission Disequilibrium of Small CNVs in Simplex Autism
Krumm, N., O’Roak, B. J., Karakoc, E., Mohajeri, K., Nelson, B., Vives, L., Jacquemont, S., Munson, J., Bernier, R., & Eichler, E. E. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.07.024 · Cited by 113 · see citing works
15q11.2 microdeletion – Seven new patients with delayed development and/or behavioural problems
von der Lippe, C., Rustad, C., Heimdal, K., & Rødningen, O. K. (2011) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2010.12.008 · Cited by 86 · see citing works
Flagged first, then by citations
Research works printed but not linked: 37
- Abdelmoity AT LePichon JB Nyp SS Soden SE Daniel CA Yu S 2012 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features J Dev Behav Pediatr 33 570 6 22922608
- Burnside RD Pasion R Mikhail FM Carroll AJ Robin NH Youngs EL 2011 Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay Hum Genet 130 517 28 21359847 PMC6814187
- Butler MG Bittel DC Kibiryeva N Talebizadeh Z Thompson T 2004 Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy Pediatrics 113 565 73 14993551 PMC6743499
- CDC 2012 Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008 MMWR Surveill Summ 61 1 19 22456193
- CDC, C.f.D.C 2006 Mental health in the United States: parental report of diagnosed autism in children aged 4-17 years--United States, 2003-2004 MMWR Morb Mortal Wkly Rep 55 481 6 16675944
- Christian SL Fantes JA Mewborn SK Huang B Ledbetter DH 1999 Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13) Hum Mol Genet 8 1025 37 10332034
- Colella S Yau C Taylor JM Mirza G Butler H Clouston P 2007 QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data Nucleic Acids Res 35 2013 25 17341461 PMC1874617
- Cook EH Jr Lindgren V Leventhal BL Courchesne R Lincoln A Shulman C 1997 Autism or atypical autism in maternally but not paternally derived proximal 15q duplication Am J Hum Genet 60 928 34 9106540 PMC1712464
- Cooper GM Coe BP Girirajan S Rosenfeld JA Vu TH Baker C 2011 A copy number variation morbidity map of developmental delay Nat Genet 43 838 46 21841781 PMC3171215
- Devlin B Scherer SW 2012 Genetic architecture in autism spectrum disorder Curr Opin Genet Dev 22 229 37 22463983
- Elliott CD 2007 Differential Ability Scale, Second edition San Antonio, TX Psychological Corporation
- Fischbach GD Lord C 2010 The Simons Simplex Collection: a resource for identification of autism genetic risk factors Neuron 68 192 5 20955926
- Girirajan S Dennis MY Baker C Malig M Coe BP Campbell CD 2013a Refinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder Am J Hum Genet PMC3567267 23375656
- Girirajan S Eichler EE 2010 Phenotypic variability and genetic susceptibility to genomic disorders Hum Mol Genet 19 R176 87 20807775 PMC2953748
- Girirajan S Johnson RL Tassone F Balciuniene J Katiyar N Fox K 2013b Global increases in both common and rare copy number load associated with autism Hum Mol Genet 22 2870 80 23535821 PMC3690969
- Hartley SL Maclean WE Jr Butler MG Zarcone J Thompson T 2005 Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome Am J Med Genet A 136 140 5 15940679 PMC1896317
- Hurley RS Losh M Parlier M Reznick JS Piven J 2007 The broad autism phenotype questionnaire J Autism Dev Disord 37 1679 90 17146701
- Hus V Gotham K Lord C 2012 Standardizing ADOS Domain Scores: Separating Severity of Social Affect and Restricted and Repetitive Behaviors J Autism Dev Disord PMC3612387 23143131
- Kearney HM Thorland EC Brown KK Quintero-Rivera F South ST 2011 American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants Genet Med 13 680 5 21681106
- Klei L Sanders SJ Murtha MT Hus V Lowe JK Willsey AJ 2012 Common genetic variants, acting additively, are a major source of risk for autism Mol Autism 3 9 23067556 PMC3579743
- Liu K Fast S Zawistowski M Tintle NL 2013 A geometric framework for evaluating rare variant tests of association Genet Epidemiol 37 345 57 23526307 PMC3718063
- Lord C Rutter M DiLavore PC Risi S 2006 Autism Diagnostic Observation Schedule WPS Edition Manual Los Angeles, CA Western Psychological Services
- Moreno-De-Luca D Sanders SJ Willsey AJ Mulle JG Lowe JK Geschwind DH 2012 Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts Mol Psychiatry PMC3720840 23044707
- Morrow EM Yoo SY Flavell SW Kim TK Lin Y Hill RS 2008 Identifying autism loci and genes by tracing recent shared ancestry Science 321 218 23 18621663 PMC2586171
- Murthy SK Nygren AO El Shakankiry HM Schouten JP Al Khayat AI Ridha A 2007 Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment Cytogenet Genome Res 116 135 40 17268193
- Rosenfeld JA Coe BP Eichler EE Cuckle H Shaffer LG 2013 Estimates of penetrance for recurrent pathogenic copy-number variations Genet Med 15 478 81 23258348 PMC3664238
- Sanders SJ Ercan-Sencicek AG Hus V Luo R Murtha MT Moreno-De-Luca D 2011 Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism Neuron 70 863 85 21658581 PMC3939065
- Sanders SJ Murtha MT Gupta AR Murdoch JD Raubeson MJ Willsey AJ 2012 De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 485 237 41 22495306 PMC3667984
- Sempere Perez A Manchon Trives I Palazon Azorin I Alcaraz Mas L Perez Lledo E Galan Sanchez F 2011 15Q11.2 (BP1-BP2) microdeletion, a new syndrome with variable expressivity An Pediatr (Barc) 75 58 62 21419731
- Shen Y Dies KA Holm IA Bridgemohan C Sobeih MM Caronna EB 2010 Clinical genetic testing for patients with autism spectrum disorders Pediatrics 125 e727 35 20231187 PMC4247857
- Sparrow SS Cicchetti DV Bella DA 2005 Vineland Adaptive Behavior Scales—2nd edition manual 2nd Minneapolis, MN NCS Pearson, Inc
- Stefansson H Rujescu D Cichon S Pietilainen OP Ingason A Steinberg S 2008 Large recurrent microdeletions associated with schizophrenia Nature PMC2687075 18668039
- van der Zwaag B Staal WG Hochstenbach R Poot M Spierenburg HA de Jonge MV 2010 A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder Am J Med Genet B Neuropsychiatr Genet 153B 960 6 20029941 PMC2933514
- Vassos E Collier DA Holden S Patch C Rujescu D St Clair D 2010 Penetrance for copy number variants associated with schizophrenia Hum Mol Genet 19 3477 81 20587603
- Wang K Li M Hadley D Liu R Glessner J Grant SF 2007 PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data Genome Res 17 1665 74 17921354 PMC2045149
- Wechsler D 2004 The Wechsler intelligence scale for children—fourth edition London Pearson Assessment
- Weiss LA Shen Y Korn JM Arking DE Miller DT Fossdal R 2008 Association between microdeletion and microduplication at 16p11.2 and autism N Engl J Med 358 667 75 18184952
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The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review
Cox, D., & Butler, M. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16024068 · Cited by 243 · see citing works
“They reported an overall modest effect for this copy number variant for autism in studying a sample of 2525 families with autism [32].”
BackgroundResultInfluentialClinical and genetic aspects of the 15q11.2 BP1–BP2 microdeletion disorder
Butler, M. G. (2017) · Journal of Intellectual Disability Research · doi:10.1111/jir.12382 · Cited by 102 · see citing works
Jønch, A. E., Douard, E., Moreau, C., Van Dijck, A., Passeggeri, M., Kooy, F., Puechberty, J., Campbell, C., Sanlaville, D., Lefroy, H., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105879 · Cited by 75 · see citing works
- Authors
- Chaste, P., Sanders, S. J., Mohan, K. N., Klei, L., Song, Y., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., Moreno‐De‐Luca, D., Yu, T. W., Fombonne, E., Geschwind, D., Grice, D. E., Ledbetter, D. H., Lord, C., Mane, S. M., Martin, D. M., Morrow, E. M., Walsh, C. A., Sutcliffe, J. S., State, M. W., Martin, C. L., Devlin, B., Beaudet, A. L., Cook, E. H., & Kim, S.
- Affiliations
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Yale University (US)
- Department of Psychology University of Michigan Ann Arbor Michigan
- University of California, Los Angeles (US)
- Boston Children's Hospital (US)
- Oregon Health & Science University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Geisinger Medical Center (US)
- Weill Cornell Medicine (US)
- University of Michigan (US)
- Brown University (US)
- Vanderbilt University (US)
- University of Illinois Chicago (US)
- University of Washington (US)
- Corresponding author
- Chaste, Pauline
- Kim, Soo‐Jeong
- ORCID
- Chaste, Pauline
- Sanders, Stephan J.
- Mohan, Kommu N.
- Klei, Lambertus
- Lowe, Jennifer K.
- Willsey, A. Jeremy
- Moreno‐De‐Luca, Daniel
- Yu, Timothy W.
- Fombonne, Eric
- Geschwind, Daniel
- Grice, Dorothy E.
- Ledbetter, David H.
- Lord, Catherine
- Mane, Shrikant M.
- Martin, Donna M.
- Morrow, Eric M.
- Walsh, Christopher A.
- Sutcliffe, James S.
- State, Matthew W.
- Devlin, Bernie
- Beaudet, Arthur L.
- Cook, Edwin H.
- Kim, Soo‐Jeong
- Venue
- Autism Research
- Publisher
- Wiley
- Published
- 2014-05-12
- Volume
- 7
- Issue
- 3
- Pages
- 355-362
- ISSN
- 1939-3792 (ISSN-L)
- 1939-3806
- PMC
- PMC6003409
- OpenAlex
- W1883254189
- Cited by
- 61
- References
- 11
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 4
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autism Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- Simons Foundation (SFARI 124827)
- NIH (K23MH082883, R01HD065272, R01MH089390)
- CIHR
- HHMI
- Fondamental Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, copy number variation, penetrance, transmission disequilibrium test, recurrence risk, variants of uncertain significance, maternal inheritance, sex differences, pathogenicity classification
- MeSH terms
- Adult, Child, Child Development Disorders, Pervasive, Chromosome Deletion, Chromosomes, Human, Pair 15, Female, Humans, Male, Genetic Predisposition to Disease, DNA Copy Number Variations
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