High-resolution chromosomal microarray analysis for copy-number variations in high-functioning autism reveals large aberration typical for intellectual disability

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.

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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

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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.

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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.

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Correspondence to Edna Grünblatt or Susanne Walitza.

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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.

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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

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Keywords

  • Autism spectrum disorder
  • High-functioning autism
  • Copy-number variation
  • Intellectual disability