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Neuropediatrics 2019; 50(06): 367-377
DOI: 10.1055/s-0039-1694797
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Identification of Copy Number Variation by Array-CGH in Portuguese Children and Adolescents Diagnosed with Autism Spectrum Disorders

S. Monteiro
1   Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
2   MMED, Master's Degree in Medicine, University of Porto, Porto, Portugal
,
J. Pinto
1   Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
3   i3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
,
A. Mira Coelho
4   Department of Child Psychiatry Consultation, Centro hospitalar de São João (CHSJ) Porto, Porto, Portugal
,
M. Leão
1   Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
5   Department of Neurogenetic Consultation, Centro hospitalar de São João (CHSJ) Porto, Porto, Portugal
,
S. Dória 
1   Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
3   i3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
› Author Affiliations
Further Information

Publication History

11 March 2019

01 July 2019

Publication Date:
09 August 2019 (online)

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Abstract

Background Autism spectrum disorders (ASD) affect many children with an estimated prevalence of 1%. Array-comparative genomic hybridization (CGH) offers significant sensitivity for the identification of submicroscopic chromosomal abnormalities and it is one of the most used techniques in daily practice. The main objective of this study was to describe the usefulness of array-CGH in the etiologic diagnosis of ASD.

Methods Two-hundred fifty-three patients admitted to a neurogenetic outpatient clinic and diagnosed with ASD were selected for array-CGH (4 × 180K microarrays). Public databases were used for classification in accordance with the American College of Medical Genetics Standards and Guidelines.

Results About 3.56% (9/253) of copy number variations (CNVs) were classified as pathogenic. When likely pathogenic CNVs were considered, the rate increased to 11.46% (29/253). Some CNVs apparently not correlated to the ASD were also found. Considering a phenotype–genotype correlation, the patients were divided in two groups. One group according to previous literature includes all the CNVs related to ASDs (23 CNVs present in 22 children) and another with those apparently not related to ASD (10 CNVs present in 7 children). In 18 patients, a next-generation sequencing (NGS) panel were performed. From these, one pathogenic and 16 uncertain significance variants were identified.

Conclusion The results of our study are in accordance with the literature, highlighting the relevance of array-CGH in the genetic of diagnosis of ASD population, namely when associated with other features. Our study also reinforces the need for complementarity between array-CGH and NGS panels or whole exome sequencing in the etiological diagnosis of ASD.

Keywords

array-comparative genomic hybridization - copy number variation - next-generation sequencing - autistic spectrum disorders
 

  • References

  • 1 Kumar RA, Christian SL. Genetics of autism spectrum disorders. Curr Neurol Neurosci Rep 2009; 9 (03) 188-197
    CrossrefPubMedGoogle Scholar
  • 2 Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. Autism: cause factors, early diagnosis and therapies. Rev Neurosci 2014; 25 (06) 841-850
    PubMedGoogle Scholar
  • 3 Bergbaum A, Ogilvie CM. Autism and chromosome abnormalities-a review. Clin Anat 2016; 29 (05) 620-627
    CrossrefPubMedGoogle Scholar
  • 4 Bremer A, Giacobini M, Eriksson M. , et al. Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 2011; 156 (02) 115-124
    CrossrefPubMedGoogle Scholar
  • 5 Jeste SS, Geschwind DH. Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol 2014; 10 (02) 74-81
    PubMedGoogle Scholar
  • 6 Kharbanda M, Tolmie J, Joss S. How to use… microarray comparative genomic hybridisation to investigate developmental disorders. Arch Dis Child Educ Pract Ed 2015; 100 (01) 24-29
    CrossrefPubMedGoogle Scholar
  • 7 Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. ; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011; 13 (07) 680-685
    PubMedGoogle Scholar
  • 8 Shinawi M, Cheung SW. The array CGH and its clinical applications. Drug Discov Today 2008; 13 (17-18): 760-770
    CrossrefPubMedGoogle Scholar
  • 9 Huang Y, Shah V, Liu T, Keshvara L. Signaling through disabled 1 requires phosphoinositide binding. Biochem Biophys Res Commun 2005; 331 (04) 1460-1468
    CrossrefPubMedGoogle Scholar
  • 10 Sánchez-Sánchez SM, Magdalon J, Griesi-Oliveira K. , et al. Rare RELN variants affect Reelin-DAB1 signal transduction in autism spectrum disorder. Hum Mutat 2018; 39 (10) 1372-1383
    CrossrefPubMedGoogle Scholar
  • 11 Li J, Liu J, Zhao L. , et al. Association study between genes in Reelin signaling pathway and autism identifies DAB1 as a susceptibility gene in a Chinese Han population. Prog Neuropsychopharmacol Biol Psychiatry 2013; 44: 226-232
    CrossrefPubMedGoogle Scholar
  • 12 Mefford HC, Sharp AJ, Baker C. , et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008; 359 (16) 1685-1699
    CrossrefPubMedGoogle Scholar
  • 13 Brunetti-Pierri N, Berg JS, Scaglia F. , et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 2008; 40 (12) 1466-1471
    CrossrefPubMedGoogle Scholar
  • 14 Dolcetti A, Silversides CK, Marshall CR. , et al. 1q21.1 Microduplication expression in adults. Genet Med 2013; 15 (04) 282-289
    PubMedGoogle Scholar
  • 15 Gourari I, Schubert R, Prasad A. 1q21.1 Duplication syndrome and epilepsy: Case report and review. Neurol Genet 2018; 4 (01) e219
    CrossrefPubMedGoogle Scholar
  • 16 Frints SG, Marynen P, Hartmann D. , et al. CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum Mol Genet 2003; 12 (13) 1463-1474
    CrossrefPubMedGoogle Scholar
  • 17 Leshchyns’ka I, Sytnyk V, Richter M, Andreyeva A, Puchkov D, Schachner M. The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron 2006; 52 (06) 1011-1025
    CrossrefPubMedGoogle Scholar
  • 18 Shuib S, McMullan D, Rattenberry E. , et al. Microarray based analysis of 3p25-p26 deletions (3p- syndrome). Am J Med Genet A 2009; 149A (10) 2099-2105
    CrossrefPubMedGoogle Scholar
  • 19 Medina M, Marinescu RC, Overhauser J, Kosik KS. Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 2000; 63 (02) 157-164
    CrossrefPubMedGoogle Scholar
  • 20 Lu Q, Aguilar BJ, Li M, Jiang Y, Chen YH. Genetic alterations of δ-catenin/NPRAP/Neurojungin (CTNND2): functional implications in complex human diseases. Hum Genet 2016; 135 (10) 1107-1116
    CrossrefPubMedGoogle Scholar
  • 21 Sundararajan T, Manzardo AM, Butler MG. Functional analysis of schizophrenia genes using GeneAnalytics program and integrated databases. Gene 2018; 641: 25-34
    CrossrefPubMedGoogle Scholar
  • 22 Arora V, Pecoraro V, Aller MI, Román C, Paternain AV, Lerma J. Increased Grik4 gene dosage causes imbalanced circuit output and human disease-related behaviors. Cell Reports 2018; 23 (13) 3827-3838
    CrossrefPubMedGoogle Scholar
  • 23 Aller MI, Pecoraro V, Paternain AV, Canals S, Lerma J. Increased dosage of high-affinity Kainate receptor gene GRIK4 alters synaptic transmission and reproduces autism spectrum disorders features. J Neurosci 2015; 35 (40) 13619-13628
    CrossrefPubMedGoogle Scholar
  • 24 Pickard BS, Malloy MP, Christoforou A. , et al. Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Mol Psychiatry 2006; 11 (09) 847-857
    PubMedGoogle Scholar
  • 25 Cafferkey M, Ahn JW, Flinter F, Ogilvie C. Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome. Am J Med Genet A 2014; 164A (08) 1916-1922
    PubMedGoogle Scholar
  • 26 Bittel DC, Kibiryeva N, Butler MG. Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome. Pediatrics 2006; 118 (04) e1276-e1283
    CrossrefPubMedGoogle Scholar
  • 27 Butler MG. Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder. J Intellect Disabil Res 2017; 61 (06) 568-579
    CrossrefPubMedGoogle Scholar
  • 28 Steinman KJ, Spence SJ, Ramocki MB. , et al; Simons VIP Consortium. 16p11.2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A 2016; 170 (11) 2943-2955
    CrossrefPubMedGoogle Scholar
  • 29 Goldenberg P. An update on common chromosome microdeletion and microduplication syndromes. Pediatr Ann 2018; 47 (05) e198-e203
    CrossrefPubMedGoogle Scholar
  • 30 Wenger TL, Miller JS, DePolo LM. , et al. 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening. Mol Autism 2016; 7 (01) 27
    CrossrefPubMedGoogle Scholar
  • 31 Nava C, Lamari F, Héron D. , et al. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry 2012; 2: e179
    CrossrefPubMedGoogle Scholar
  • 32 Jacquemont ML, Sanlaville D, Redon R. , et al. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 2006; 43 (11) 843-849
    CrossrefPubMedGoogle Scholar
  • 33 Amado-Puentes A, Reparaz-Andrade A, Del Campo-García A. , et al. Neurodevelopmental disorders and array-based comparative genomic hybridization: sensitivity and specificity using a criteria checklist for genetic test performance. Neuropediatrics 2019; 50 (03) 164-169
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Tammimies K, Marshall CR, Walker S. , et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA 2015; 314 (09) 895-903
    CrossrefPubMedGoogle Scholar
  • 35 Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med 2013; 15 (06) 478-481
    PubMedGoogle Scholar
  • 36 Abad C, Cook MM, Cao L. , et al. A rare de novo RAI1 gene mutation affecting BDNF-enhancer-driven transcription activity associated with autism and atypical Smith-Magenis syndrome presentation. Biology (Basel) 2018; 7 (02) E31
    CrossrefPubMedGoogle Scholar
  • 37 Falco M, Amabile S, Acquaviva F. RAI1 gene mutations: mechanisms of Smith-Magenis syndrome. Appl Clin Genet 2017; 10: 85-94
    CrossrefPubMedGoogle Scholar
  • 38 Yan J, Bi W, Lupski JR. Penetrance of craniofacial anomalies in mouse models of Smith-Magenis syndrome is modified by genomic sequence surrounding Rai1: not all null alleles are alike. Am J Hum Genet 2007; 80 (03) 518-525
    CrossrefPubMedGoogle Scholar
  • 39 Jiang YH, Yuen RK, Jin X. , et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet 2013; 93 (02) 249-263
    CrossrefPubMedGoogle Scholar
  • 40 de Ligt J, Willemsen MH, van Bon BW. , et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367 (20) 1921-1929
    CrossrefPubMedGoogle Scholar