Abstract
Copy-number variants (CNVs), in particular rare, small and large ones (< 1% frequency) and those encompassing brain-related genes, have been shown to be associated with neurodevelopmental disorders like autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). However, the vast majority of CNV findings lack specificity with respect to autistic or developmental-delay phenotypes. Therefore, the aim of the study was to investigate the size and frequency of CNVs in high-functioning ASD (HFA) without ID compared with a random population sample and with published findings in ASD and ID. To investigate the role of CNVs for the “core symptoms” of high-functioning autism, we included in the present exploratory study only patients with HFA without ID. The aim was to test whether HFA have similar large rare (> 1 Mb) CNVs as reported in ASD and ID. We performed high-resolution chromosomal microarray analysis in 108 children and adolescents with HFA without ID. There was no significant difference in the overall number of rare CNVs compared to 124 random population samples. However, patients with HFA carried significantly more frequently CNVs containing brain-related genes. Surprisingly, six HFA patients carried very large CNVs known to be typically present in ID. Our findings provide new evidence that not only small, but also large CNVs affecting several key genes contribute to the genetic etiology/risk of HFA without affecting their intellectual ability.
Similar content being viewed by others
Availability of data and materials
The data sets generated and/or analyzed during the current study are not publicly available due to limits in consents, but are available from the corresponding author on reasonable request.
Abbreviations
- ADAD2 :
-
Adenosine deaminase domain containing 2
- ADCY9 :
-
Adenylate cyclase 8
- ADHD:
-
Attention deficit hyperactivity disorder
- AHI1 :
-
Abelson helper integration site 1
- ARL13B :
-
ADP-ribosylation factor-like 13B
- ARL6 :
-
ADP-riboylation factor-like 6
- ASAP1 :
-
ArfGAP with SH3 domain, ankyrin repeat, and PH domain 1
- ASD:
-
Autism spectrum disorder
- BBS:
-
Bardet–Biedl syndrome
- BRD1:
-
Bromodomain-containing protein 1
- CBCL:
-
Child behavior checklist
- CC2D2A :
-
Coiled-coil and C2 domain containing 2A
- Celsr1 :
-
Cadherin, EGF LAG seven-pass G-type receptor 1
- CEP290 :
-
Centrosomal protein 290
- ChAS:
-
Chromosome analysis suite
- CMA:
-
Chromosomal microarray analysis
- CNS:
-
Central nervous system
- CNV:
-
Copy-number variant
- COL22A1 :
-
Collagen, Type XXII, alpha 1
- CRYBG3 :
-
Crystallin beta-gamma domain containing 3
- DD:
-
Developmental delay
- DGV:
-
Database of genomic variants
- DHFRL1 :
-
Dihydrofolate reductase-like 1
- DNA:
-
Deoxyribonucleic acid
- EPHA6 :
-
EPH Receptor A6
- FAM135B :
-
C8orfK32, family with sequence similarity 135 member B
- FAM19A5 :
-
Family sequence similarity 19
- FARP2 :
-
FERM, RhoGEF, and pleckstrin domain-containing protein
- GABRR3 :
-
Gamma-aminobutyric acid (GABA) A receptor, Rho 3
- GRAMD4 :
-
GRAM domain containing 4
- GWAS:
-
Genome-wide association study
- HDAC4 :
-
Histone deacetylase 4
- HDLBP :
-
High-density lipoprotein binding protein
- HFA:
-
High-functioning autism
- ID:
-
Intellectual disability
- INPP5E :
-
Inositol polyphosphate-5-phosphatase E
- IQ:
-
Intelligence quotient
- Kb:
-
Kilobyte
- KCNG4 :
-
Potassium voltage-gated channel subfamily KQT member 4
- KCNQ3 :
-
Potassium channel, voltage-gated KQT-like subfamily Q, member 3
- KHDRBS3:
-
KH domain containing, RNA binding, signal transduction associated 3
- LOC150935 :
-
Uncharacterized LOC150935
- MAPK8IP2 :
-
Mitogen-activated protein kinase 8 interacting protein 2
- Mb:
-
Megabyte
- MINA :
-
MYC-induced nuclear antigen
- NPHP1 :
-
Nephrocystin-1
- NRXN1:
-
Neurexin-1-alpha
- NSUN3 :
-
NOP2/sun domain family, member 3
- OCD:
-
Obsessive-compulsive disorder
- PASK :
-
Proline-alanine-rich STE2 0-related kinase
- PLXNB2 :
-
Plexin B2
- PROS1 :
-
Protein S
- PTCHD1:
-
Patched domain containing 1
- RPGRIP1L :
-
Retinitis pigmentosa GTPase regulator interacting protein 1 like
- SCO2 :
-
SCO2 cytochrome c oxidase assembly
- SCQ:
-
Social communication questionnaire
- SHANK2:
-
SH3 and multiple ankyrin repeat domains protein 2
- SHANK3:
-
SH3 and multiple ankyrin repeat domains protein 3
- STX19 :
-
Syntaxin 19
- TBC1D22A :
-
TBC1 domain family, member 22A
- TMEM67/MKS3 :
-
Transmembrane protein-67
- TTLL8 :
-
Tubulin tyrosine ligase-like family member 8
- TUBGCP6 :
-
Tubulin, gamma complex associated protein 6
- TYMP :
-
Thymidine phosphorylase
- VSTM4 :
-
V-Set and Transmembrane Domain Containing 4
- WBCR:
-
Williams–Beuren critical region
- WBS:
-
Williams–Beuren syndrome
References
Aldinger KA, Kogan J, Kimonis V, Fernandez B, Horn D, Klopocki E, Chung B, Toutain A, Weksberg R, Millen KJ, Barkovich AJ, Dobyns WB (2013) Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion. Am J Med Genet A 161(1):131–136. https://doi.org/10.1002/ajmg.a.35700
Allach El Khattabi L, Heide S, Caberg J-H, Andrieux J, Doco Fenzy M, Vincent-Delorme C, Callier P, Chantot-Bastaraud S, Afenjar A, Boute-Benejean O, Pierre Cordier M, Faivre L, Francannet C, Gerard M, Goldenberg A, Masurel-Paulet A, Mosca-Boidron A-L, Marle N, Anne M, Pipiras E (2018) 16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations. J Med Genet. https://doi.org/10.1136/jmedgenet-2018-105389
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 5th edn. APA, Washington DC
Asadollahi R, Oneda B, Joset P, Azzarello-Burri S, Bartholdi D, Steindl K, Vincent M, Cobilanschi J, Sticht H, Baldinger R, Reissmann R, Sudholt I, Thiel CT, Ekici AB, Reis A, Bijlsma EK, Andrieux J, Dieux A, FitzPatrick D, Ritter S, Baumer A, Latal B, Plecko B, Jenni OG, Rauch A (2014) The clinical significance of small copy number variants in neurodevelopmental disorders. J Med Genet 51(10):677–688. https://doi.org/10.1136/jmedgenet-2014-102588
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25(1):25–29. https://doi.org/10.1038/75556
Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ (2004) Autism and abnormal development of brain connectivity. J Neurosci 24(42):9228–9231. https://doi.org/10.1523/JNEUROSCI.3340-04.2004
Berg JS, Brunetti-Pierri N, Peters SU, Kang S-HL, Fong C-T, Salamone J, Freedenberg D, Hannig VL, Prock LA, Miller DT, Raffalli P, Harris DJ, Erickson RP, Cunniff C, Clark GD, Blazo MA, Peiffer DA, Gunderson KL, Sahoo T, Patel A, Lupski JR, Beaudet AL, Cheung SW (2007) Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet Med 9(7):427–441
Bölte S, Poustka F (2006) Fragebogen zur Sozialen Kommunikation - Autismus-Screening; Deutsche Fassung des Social Communication Questionnaire (SCQ). Verlag Hans Huber, Bern
Bölte S, Crecelius K, Poustka F (2000) Der Fragebogen über Verhalten und soziale Kommunikation (VSK). https://doi.org/10.1026//0012-1924.46.3.149
Bölte S, Le Couteur A, Lord C, Rutter M (2006) Diagnostisches Interview für Autismus-revidiert: ADI-R; deutsche Fassung des Autism diagnostic interview-revised (ADI-R) von Michael Rutter, Ann Le Couteur und Catherine Lord; Manual. Huber
Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, Zuffardi O (2001) Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet 69(2):261–268. https://doi.org/10.1086/321293
Chiang H-M, Tsai LY, Cheung YK, Brown A, Li H (2014) A meta-analysis of differences in IQ profiles between individuals with asperger’s disorder and high-functioning autism. J Autism Dev Disord 44(7):1577–1596. https://doi.org/10.1007/s10803-013-2025-2
Chiocchetti AG, Kopp M, Waltes R, Haslinger D, Duketis E, Jarczok TA, Poustka F, Voran A, Graab U, Meyer J, Klauck SM, Fulda S, Freitag CM (2015) Variants of the CNTNAP2 5’ promoter as risk factors for autism spectrum disorders: a genetic and functional approach. Mol Psychiatry 20(7):839–849. https://doi.org/10.1038/mp.2014.103
Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, Gillan N, Hallett V, Lietz S, Garnett T, Ronald A, Plomin R, Rijsdijk F, Happe F, Bolton P (2015) Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry 72(5):415–423. https://doi.org/10.1001/jamapsychiatry.2014.3028
Consortium IMGSoA (2001) A genome-wide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 69(3):570–581
Curry CJ, Mao R, Aston E, Mongia SK, Treisman T, Procter M, Chou B, Whitby H, South ST, Brothman AR (2008) Homozygous deletions of a copy number change detected by array CGH: a new cause for mental retardation? Am J Med Genet A 146A(15):1903–1910. https://doi.org/10.1002/ajmg.a.32450
Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B, Trouillard O, Nygren G, Kopp S, Johansson M, Rastam M, Burglen L, Leguern E, Verloes A, Leboyer M, Brice A, Gillberg C, Betancur C (2009) Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry 66(4):349–359. https://doi.org/10.1016/j.biopsych.2009.01.025
Devillard F, Guinchat V, Moreno-De-Luca D, Tabet A-C, Gruchy N, Guillem P, Nguyen Morel M-A, Leporrier N, Leboyer M, Jouk P-S, Lespinasse J, Betancur C (2010) Paracentric inversion of chromosome 2 associated with cryptic duplication of 2q14 and deletion of 2q37 in a patient with autism. Am J Med Genet A 152A(9):2346–2354. https://doi.org/10.1002/ajmg.a.33601
Dilling H, Freyberger HJ, Stieglitz RD (1996) ICD-10 field trial of the diagnostic criteria for research in German-speaking countries. Introduction. Psychopathology 29(5):258–259
Doherty ES, Lacbawan FL (1993) 2q37 Microdeletion Syndrome. In: Pagon RA, Adam MP, Ardinger HH et al. (eds) GeneReviews (R). University of Washington, Seattle All rights reserved., Seattle (WA)
Döpfner M, Lehmkuhl G (2000) FBB-HKS [Rating-scale for hyperkinetic disorder from the diagnostic system for mental disorders in childhood and adolescence according to ICD-10 and DSM-IV (DISYPS-KJ)], 2nd edn. Hofgrefe: Göttingen, Germany
Döpfner M, Plück J, Bölte S, Lenz K, Melchers P, Heim K (eds) (1998) Arbeitsgruppe Kinder- und Jugendlichen- und Familiendiagnostik: Child Behavior Checklist (CBCL); Elternfragebogen über das Verhalten von Kindern und Jugendlichen, 2nd edn. Arbeitsgruppe Kinder-, Jugend- und Familiendiagnostik KJFD, Köln
Edgar R, Domrachev M, Lash AE (2002) Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30(1):207–210. https://doi.org/10.1093/nar/30.1.207
Egger JI, Zwanenburg RJ, van Ravenswaaij-Arts CM, Kleefstra T, Verhoeven WM (2016) Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: implications for treatment strategy. Genes Brain Behav. https://doi.org/10.1111/gbb.12285
Felder B, Radlwimmer B, Benner A, Mincheva A, Tödt G, Beyer KS, Schuster C, Bölte S, Schmötzer G, Klauck SM, Poustka F, Lichter P, Poustka A (2009) FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome. Am J Med Genet A 149A(5):952–959. https://doi.org/10.1002/ajmg.a.32779
Fernandez BA, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P, Joseph-George AM, MacKay S, Whitten K, Noble B (2009) Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11. 2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet 47(3):195–203. https://doi.org/10.1136/jmg.2009.069369
Frazier TW, Thompson L, Youngstrom EA, Law P, Hardan AY, Eng C, Morris N (2014) A twin study of heritable and shared environmental contributions to autism. J Autism Dev Disord 44(8):2013–2025. https://doi.org/10.1007/s10803-014-2081-2
Freitag CM, Staal W, Klauck SM, Duketis E, Waltes R (2010) Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry 19(3):169–178. https://doi.org/10.1007/s00787-009-0076-x
Fujitani M, Zhang S, Fujiki R, Fujihara Y, Yamashita T (2017) A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484/protocadherin-19 signaling. Mol Psychiatry 22(3):364–374. https://doi.org/10.1038/mp.2016.106
Gazzellone MJ, Zarrei M, Burton CL, Walker S, Uddin M, Shaheen SM, Coste J, Rajendram R, Schachter RJ, Colasanto M, Hanna GL, Rosenberg DR, Soreni N, Fitzgerald KD, Marshall CR, Buchanan JA, Merico D, Arnold PD, Scherer SW (2016) Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation. J Neurodev Disord 8:36. https://doi.org/10.1186/s11689-016-9170-9
Gillberg C (1998) Asperger syndrome and high-functioning autism. Br J Psychiatry 172(3):200–209. https://doi.org/10.1192/bjp.172.3.200
Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70(5):898–907. https://doi.org/10.1016/j.neuron.2011.05.021
Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, Shafer N, Bernier R, Ferrero GB, Silengo M (2011) Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet 7(11):e1002334
Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD, Mark K, Vu TH, Alkan C, Cheng Z (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92(2):221–237
Grünblatt E, Oneda B, Ekici AB, Ball J, Geissler J, Uebe S, Romanos M, Rauch A, Walitza S (2017) High resolution chromosomal microarray analysis in paediatric obsessive-compulsive disorder. BMC Med Genom 10(1):68. https://doi.org/10.1186/s12920-017-0299-5
GTEx Consortium (2013) The Genotype-tissue expression (GTEx) project. Nat Genet 45(6):580–585. https://doi.org/10.1038/ng.2653
Guilherme RS, Soares KC, Simioni M, Vieira TP, Gil-da-Silva-Lopes VL, Kim CA, Brunoni D, Spinner NB, Conlin LK, Christofolini DM, Kulikowski LD, Steiner CE, Melaragno MI (2014) Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion. Am J Med Genet A 164(7):1659–1665. https://doi.org/10.1002/ajmg.a.36512
Guo J, Otis JM, Higginbotham H, Monckton C, Cheng J, Asokan A, Mykytyn K, Caspary T, Stuber GD, Anton ES (2017) Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity. Dev Cell 42(3):286–300. https://doi.org/10.1016/j.devcel.2017.07.010
Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102
Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns JP, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight SJ, Eichler EE, Vermeesch JR (2009) Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46(4):223–232. https://doi.org/10.1136/jmg.2007.055202
Imitola J, Khurana DS, Teplyuk NM, Zucker M, Jethva R, Legido A, Krichevsky AM, Frangieh M, Walsh CA, Carvalho KS (2015) A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly. Am J Med Genet A 167(11):2808–2816. https://doi.org/10.1002/ajmg.a.37268
Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, Moreno-De-Luca D, Moreno-De-Luca A, Mulle JG, Warren ST (2011) An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med 13(9):777–784
Kaufman AS, Kaufman NL, Melchers P, Preuss U (2009) Kaufman Assessment Battery for Children, Deutsche Version. Individualtest zur Messung von Intelligenz und Fertigkeit bei Kindern. Hogrefe
Lai M-C, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S (2015) Sex/gender differences and autism: setting the scene for future research. J Am Acad Child Adolesc Psychiatry 54(1):11–24. https://doi.org/10.1016/j.jaac.2014.10.003
Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemiere N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T (2014) Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet 10(9):e1004580. https://doi.org/10.1371/journal.pgen.1004580
Leroy C, Landais E, Briault S, David A, Tassy O, Gruchy N, Delobel B, Gregoire M-J, Leheup B, Taine L, Lacombe D, Delrue M-A, Toutain A, Paubel A, Mugneret F, Thauvin-Robinet C, Arpin S, Le Caignec C, Jonveaux P, Beri M, Leporrier N, Motte J, Fiquet C, Brichet O, Mozelle-Nivoix M, Sabouraud P, Golovkine N, Bednarek N, Gaillard D, Doco-Fenzy M (2013) The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur J Hum Genet 21(6):602–612. https://doi.org/10.1038/ejhg.2012.230
Lord C, Rutter M, Le Couteur A (1994) Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24(5):659–685
Lord C, Rutter M, DiLavore PC, Risi S, Gotham K, Bishop S (2012) Autism diagnostic observation schedule: ADOS-2. Western Psychological Services Los Angeles
Lowe JK, Werling DM, Constantino JN, Cantor RM, Geschwind DH (2015) Quantitative linkage analysis to the autism endophenotype social responsiveness identifies genome-wide significant linkage to two regions on chromosome 8. Am J Psychiatry 172(3):266–275. https://doi.org/10.1176/appi.ajp.2014.14050576
Marshall CR, Scherer SW (2012) Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol Biol 838:115–135. https://doi.org/10.1007/978-1-61779-507-7_5
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82(2):477–488. https://doi.org/10.1016/j.ajhg.2007.12.009
Mefford HC, Batshaw ML, Hoffman EP (2012) Genomics, intellectual disability, and autism. N Engl J Med 366(8):733–743. https://doi.org/10.1056/NEJMra1114194
Miceli F, Soldovieri MV, Joshi N, Weckhuysen S, Cooper EC, Taglialatela M (1993) KCNQ3-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA et al. (eds) GeneReviews((R)). University of Washington, Seattle All rights reserved., Seattle (WA)
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215
Mitz AR, Philyaw TJ, Boccuto L, Shcheglovitov A, Sarasua SM, Kaufmann WE, Thurm A (2018) Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Genet 26(3):293–302. https://doi.org/10.1038/s41431-017-0042-x
Nagamani SC, Erez A, Bader P, Lalani SR, Scott DA, Scaglia F, Plon SE, Tsai CH, Reimschisel T, Roeder E, Malphrus AD, Eng PA, Hixson PM, Kang SH, Stankiewicz P, Patel A, Cheung SW (2011) Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet 19(3):280–286. https://doi.org/10.1038/ejhg.2010.184
Nyffeler J, Walitza S, Bobrowski E, Gundelfinger R, Grünblatt E (2014) Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism. J Mol Psychiatry 2(1):1. https://doi.org/10.1186/2049-9256-2-1
Petermann F, Petermann U (2010) HAWIK-IV (3. erweiterte Auflage). Huber, Bern
Phelan K, McDermid HE (2012) The 22q133 deletion syndrome (Phelan-McDermid Syndrome). Mol Syndromol 2(3–5):186–201
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466(7304):368–372. https://doi.org/10.1038/nature09146
Pober BR (2010) Williams-Beuren syndrome. N Engl J Med 362(3):239–252. https://doi.org/10.1056/NEJMra0903074
Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC, Sato D, Rickaby J, Lu C, Szatmari P, Roberts W, Fernandez BA, Marshall CR, Hatchwell E, Eis PS, Scherer SW (2012) A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 (Bethesda) 2(12):1665–1685. https://doi.org/10.1534/g3.112.004689
Puffenberger EG, Jinks RN, Wang H, Xin B, Fiorentini C, Sherman EA, Degrazio D, Shaw C, Sougnez C, Cibulskis K (2012) A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat 33(12):1639–1646
Ramalingam A, Zhou XG, Fiedler SD, Brawner SJ, Joyce JM, Liu HY, Yu S (2011) 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J Hum Genet 56(7):541–544. https://doi.org/10.1038/jhg.2011.42
Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Ropke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schrock E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380(9854):1674–1682. https://doi.org/10.1016/S0140-6736(12)61480-9
Rosenberg RE, Law JK, Yenokyan G, McGready J, Kaufmann WE, Law PA (2009) Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med 163(10):907–914
Rühl D, Bölte S, Feineis-Matthews S, Poustka F (2004) Diagnostische Beobachtungsskala für Autistische Störungen; Deutsche Fassung der Autism Diagnostic Observation Schedule (ADOS). Verlag Hans Huber, Switzerland
Rutter M, Bailey A, Lord C, Cianchetti C, Fancello GS (2007) SCQ: Social Communication Questionnaire: Manuale. Giunti OS
Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O’Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Gunel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW (2011) Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70(5):863–885. https://doi.org/10.1016/j.neuron.2011.05.002
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) The familial risk of autism. JAMA 311(17):1770–1777. https://doi.org/10.1001/jama.2014.4144
Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D, Hawes A, Lewis L, Akbar H, Varghese R, Boerwinkle E, Gibbs RA, Zoghbi HY (2011) Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet 20(17):3366–3375. https://doi.org/10.1093/hmg/ddr243
Shishido E, Aleksic B, Ozaki N (2014) Copy-number variation in the pathogenesis of autism spectrum disorder. Psychiatry Clin Neurosci 68(2):85–95
Slavotinek A, Maher E, Gregory P, Rowlandson P, Huson SM (1997) The phenotypic effects of chromosome rearrangement involving bands 7q21.3 and 22q13.3. J Med Genet 34(10):857–861. https://doi.org/10.1136/jmg.34.10.857
Smith M, Escamilla JR, Filipek P, Bocian ME, Modahl C, Flodman P, Spence MA (2001) Molecular genetic delineation of 2q37.3 deletion in autism and osteodystrophy: report of a case and of new markers for deletion screening by PCR. Cytogenet Genome Res 94(1–2):15–22
Somerville MJ, Mervis CB, Young EJ, Seo EJ, del Campo M, Bamforth S, Peregrine E, Loo W, Lilley M, Perez-Jurado LA, Morris CA, Scherer SW, Osborne LR (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353(16):1694–1701. https://doi.org/10.1056/NEJMoa051962
Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT, Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A, Canitano R, Chaplin W, Betancur C, Buxbaum JD (2013) Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism 4(1):18. https://doi.org/10.1186/2040-2392-4-18
Tellegen P, Winkel M, Laros J (2003) Snijders oomen non-verbal intelligence test revised (SON-R). Hofgrefe-Verlag, Göttingen, Germany
Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F (2016) Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatry 57(5):585–595. https://doi.org/10.1111/jcpp.12499
Torniero C, dalla Bernardina B, Novara F, Vetro A, Ricca I, Darra F, Pramparo T, Guerrini R, Zuffardi O (2007) Cortical dysplasia of the left temporal lobe might explain severe expressive-language delay in patients with duplication of the Williams-Beuren locus. Eur J Hum Genet 15(1):62–67. https://doi.org/10.1038/sj.ejhg.5201730
Tsang KM, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, Yoshida CK, Zerbo O, Weiss LA (2013) A genome-wide survey of transgenerational genetic effects in autism. PLoS One 8(10):e76978
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419. https://doi.org/10.1126/science.1260419
Uzunova G, Pallanti S, Hollander E (2016) Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. World J Biol Psychiatry 17(3):174–186. https://doi.org/10.3109/15622975.2015.1085597
Van der Aa N, Rooms L, Vandeweyer G, van den Ende J, Reyniers E, Fichera M, Romano C, Delle Chiaie B, Mortier G, Menten B, Destree A, Maystadt I, Mannik K, Kurg A, Reimand T, McMullan D, Oley C, Brueton L, Bongers EM, van Bon BW, Pfund R, Jacquemont S, Ferrarini A, Martinet D, Schrander-Stumpel C, Stegmann AP, Frints SG, de Vries BB, Ceulemans B, Kooy RF (2009) Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 52(2–3):94–100. https://doi.org/10.1016/j.ejmg.2009.02.006
van der Zwaag B, Franke L, Poot M, Hochstenbach R, Spierenburg HA, Vorstman JA, van Daalen E, de Jonge MV, Verbeek NE, Brilstra EH, van ‘t Slot R, Ophoff RA, van Es MA, Blauw HM, Veldink JH, Buizer-Voskamp JE, Beemer FA, van den Berg LH, Wijmenga C, van Amstel HK, van Engeland H, Burbach JP, Staal WG (2009) Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One 4(5):e5324. https://doi.org/10.1371/journal.pone.0005324
Verheij JB, de Munnik SA, Dijkhuizen T, de Leeuw N, Olde Weghuis D, van den Hoek GJ, Rijlaarsdam RS, Thomasse YE, Dikkers FG, Marcelis CL, van Ravenswaaij-Arts CM (2009) An 8.35 Mb overlapping interstitial deletion of 8q24 in two patients with coloboma, congenital heart defect, limb abnormalities, psychomotor retardation and convulsions. Eur J Med Genet 52(5):353–357. https://doi.org/10.1016/j.ejmg.2009.05.006
Vissers ME, Cohen MX, Geurts HM (2012) Brain connectivity and high functioning autism: a promising path of research that needs refined models, methodological convergence, and stronger behavioral links. Neurosci Biobehav Rev 36(1):604–625. https://doi.org/10.1016/j.neubiorev.2011.09.003
Vorstman JAS, Staal WG, van Daalen E, van Engeland H, Hochstenbach PFR, Franke L (2005) Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 11 (1):18–28. doi:http://www.nature.com/mp/journal/v11/n1/suppinfo/4001757s1.html
Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459(7246):528–533. https://doi.org/10.1038/nature07999
Wassink TH, Vieland VJ, Sheffield VC, Bartlett CW, Goedken R, Childress D, Piven J (2008) Posterior probability of linkage analysis of autism dataset identifies linkage to chromosome 16. Psychiatr Genet 18(2):85–91. https://doi.org/10.1097/YPG.0b013e3282f9b48e
Wechsler D (1981) WAIS-R manual: Wechsler adult intelligence scale-revised. Psychological Corporation
Weiss R (2006) CFT 20-R: Grundintelligenztest Skala 2—Revision. Hofgrefe-Verlag, Göttingen
Werling AM, Bobrowski E, Taurines R, Gundelfinger R, Romanos M, Grünblatt E, Walitza S (2015) CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches. J Neural Transm (Vienna). https://doi.org/10.1007/s00702-015-1458-5
Wheeler PG, Huang D, Dai Z (2014) Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. Am J Med Genet A 164(7):1826–1829
Yingjun X, Haiming Y, Mingbang W, Liangying Z, Jiaxiu Z, Bing S, Qibin Y, Xiaofang S (2017) Copy number variations independently induce autism spectrum disorder. Biosci Rep. https://doi.org/10.1042/bsr20160570
Zoghbi HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302(5646):826–830. https://doi.org/10.1126/science.1089071
Acknowledgments
The authors thank the families, patients, and control volunteers who participated in this research. The authors would like to acknowledge Miryame Hofmann of the Translational Molecular Psychiatry Laboratory, Department of Child and Adolescent Psychiatry and Psychotherapy Zurich, for her technical support.
Funding
The current study was funded by the University of Zurich. The funding body was not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Author information
Authors and Affiliations
Contributions
AW and EG drafted the manuscript, performed literature search and worked on the interpretation of the data. EG participated in the study design and performed the statistical analysis. BO planned and carried out the genetic studies, worked on the interpretation of the data, and revised the manuscript. EB was involved in the clinical design, recruitment and acquisition of clinical data in Zurich. RG was involved in the supervision of the acquisition of the clinical data in Zurich and was involved in the interpretation of data. RT was involved in the clinical acquisition of data in Würzburg and interpretation of data and revised the manuscript. MR was responsible in the clinical acquisition of data in Würzburg. AR was responsible for the CNV study design, the interpretation of the data and revised the manuscript. SW was responsible for the underlying clinical study design, initiated and created together with AR the CNV study; she was involved in the interpretation of data and revised the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
SW has received in the last 5 years royalities from Thieme Hogrefe, Kohlhammer, Springer, Beltz. SW has received lecture honoraria from Opopharma in the last 5 years. Her work was supported in the last 5 years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, and Gertrud Thalmann Fonds. Outside professional activities and interests are declared under the link of the University of Zurich www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/. AR was supported by the Swiss National Science Foundation, E-rare, and Von Sick foundation. Outside professional activities and interests are declared under the link of the University of Zurich https://www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/R. The other authors declare no conflict of interest.
Ethical approval and consent to participate
All procedures were performed with the written informed consent of the parents of all participants and the study was approved by the local ethics committees of the Canton of Zurich (Switzerland, E-36/2009), and of Würzburg (Germany, study numbers 8/06 and 227/09), respectively.
Consent for publication
The aforementioned consent form includes publication consent as well.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Werling, A.M., Grünblatt, E., Oneda, B. et al. High-resolution chromosomal microarray analysis for copy-number variations in high-functioning autism reveals large aberration typical for intellectual disability. J Neural Transm 127, 81–94 (2020). https://doi.org/10.1007/s00702-019-02114-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-019-02114-9