title: The clinical significance of small copy number variants in neurodevelopmental disorders.
abstract: BACKGROUND
  Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context.
  
  
  METHODS
  By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs.
  
  
  RESULTS
  We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear.
  
  
  CONCLUSIONS
  These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions.
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Reza
authors.initials: R
authors.lastname: Asadollahi
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oneda
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Joset
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Azzarello-Burri
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Steindl
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Joana
authors.initials: J
authors.lastname: Cobilanschi
authors.affiliation: Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Rosa
authors.initials: R
authors.lastname: Baldinger
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Reissmann
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Sudholt
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Thiel
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.affiliation: Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Clinique de Génétique Guy Fontaine, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: David
authors.initials: D
authors.lastname: FitzPatrick
authors.affiliation: Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ritter
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.affiliation: Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Latal
authors.affiliation: Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.affiliation: Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Oskar G
authors.initials: OG
authors.lastname: Jenni
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D055815:Young Adult
keywords: Clinical Genetics; Copy-Number; Developmental; Diagnostics; Genome-Wide
references.citation: Genome Res. 2013 Sep;23(9):1383-94
references.pmid: 23685542
references.citation: Am J Med Genet A. 2013 Aug;161A(8):1853-9
references.pmid: 23794250
references.citation: Hum Mutat. 2010 Dec;31(12):1326-42
references.pmid: 20848651
references.citation: Amino Acids. 2004 Dec;27(3-4):269-75
references.pmid: 15592755
references.citation: Am J Hum Genet. 1999 Aug;65(2):387-96
references.pmid: 10417281
references.citation: Nat Genet. 2012 Jun 24;44(8):934-40
references.pmid: 22729224
references.citation: Hum Mol Genet. 2003 Oct 1;12(19):2491-501
references.pmid: 12915443
references.citation: Am J Hum Genet. 2009 Apr;84(4):524-33
references.pmid: 19344873
references.citation: Hum Mutat. 2013 Oct;34(10):1439-48
references.pmid: 23893877
references.citation: Eur J Hum Genet. 2014 Aug;22(8):1034-9
references.pmid: 24301056
references.citation: Nat Genet. 2011 Jun 26;43(8):729-31
references.pmid: 21706002
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Nucleic Acids Res. 2012 May;40(9):4193-202
references.pmid: 22241778
references.citation: Am J Hum Genet. 2013 Oct 3;93(4):607-19
references.pmid: 24094742
references.citation: Mol Cell Biochem. 2002 Feb;231(1-2):69-74
references.pmid: 11952167
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: Mol Cell Biol. 2013 May;33(9):1869-82
references.pmid: 23459938
references.citation: Eur J Clin Invest. 2005 Jan;35(1):38-46
references.pmid: 15638818
references.citation: Nature. 2014 Jan 16;505(7483):361-6
references.pmid: 24352232
references.citation: Curr Biol. 2003 Mar 18;13(6):510-5
references.pmid: 12646135
references.citation: Eur J Hum Genet. 2014 Jan;22(1):71-8
references.pmid: 23632794
references.citation: PLoS One. 2009 Aug 10;4(8):e6568
references.pmid: 19668335
references.citation: Eur J Hum Genet. 2011 Nov;19(11):1112-3
references.pmid: 21587321
references.citation: Am J Hum Genet. 2010 May 14;86(5):749-64
references.pmid: 20466091
references.citation: Am J Med Genet A. 2011 Oct;155A(10):2386-96
references.pmid: 22031302
references.citation: Trends Neurosci. 2014 Feb;37(2):95-105
references.pmid: 24387789
references.citation: Eur J Hum Genet. 2014 Apr;22(4):480-5
references.pmid: 23900271
references.citation: Genomics. 2000 Jan 15;63(2):157-64
references.pmid: 10673328
references.citation: Neuron. 2009 Nov 12;64(3):320-7
references.pmid: 19914181
references.citation: Hum Genet. 2000 Aug;107(2):165-75
references.pmid: 11030415
references.citation: Am J Hum Genet. 2005 Feb;76(2):312-26
references.pmid: 15635506
references.citation: Am J Hum Genet. 2013 Oct 3;93(4):595-606
references.pmid: 24035194
references.citation: Cell Mol Life Sci. 2007 Jun;64(12):1558-70
references.pmid: 17514357
references.citation: Cell. 2006 Jun 2;125(5):971-86
references.pmid: 16751105
references.citation: Nature. 2010 Jul 15;466(7304):368-72
references.pmid: 20531469
references.citation: EMBO J. 2007 Apr 18;26(8):2005-14
references.pmid: 17396146
references.citation: Annu Rev Genomics Hum Genet. 2010;11:161-87
references.pmid: 20822471
references.citation: Genet Med. 2012 Jun;14(6):594-603
references.pmid: 22382802
references.citation: Mol Cell. 2006 Aug;23(4):561-74
references.pmid: 16916643
references.citation: Nat Genet. 2011 Aug 14;43(9):838-46
references.pmid: 21841781
references.citation: Eur J Med Genet. 2011 Mar-Apr;54(2):144-51
references.pmid: 21094706
references.citation: Methods Mol Biol. 2000;143:97-129
references.pmid: 11084904
references.citation: Am J Med Genet A. 2011 Jun;155A(6):1336-51
references.pmid: 21548129
references.citation: J Med Genet. 2011 Nov;48(11):741-51
references.pmid: 21954287
references.citation: Prog Lipid Res. 2010 Oct;49(4):366-77
references.pmid: 20470824
references.citation: Neuron. 2006 Oct 5;52(1):103-21
references.pmid: 17015230
references.citation: Eur J Hum Genet. 2013 Oct;21(10):1100-4
references.pmid: 23403903
references.citation: Am J Hum Genet. 2013 Feb 7;92(2):221-37
references.pmid: 23375656
references.citation: Eur J Med Genet. 2009 Nov-Dec;52(6):398-403
references.pmid: 19765681
references.citation: Eur J Hum Genet. 2009 Jul;17(7):911-8
references.pmid: 19050731
references.citation: Hum Mutat. 2007 Jul;28(7):732-8
references.pmid: 17377962
references.citation: Am J Hum Genet. 2008 Oct;83(4):504-10
references.pmid: 18940311
references.citation: Biochem Biophys Res Commun. 2002 Nov 22;299(1):49-56
references.pmid: 12435388
references.citation: Neuron. 2008 Feb 7;57(3):364-77
references.pmid: 18255030
references.citation: Lancet. 2012 Nov 10;380(9854):1674-82
references.pmid: 23020937
references.citation: Eur J Hum Genet. 2014 Jan;22(1):40-5
references.pmid: 23695280
references.citation: Neuron. 2011 Jun 23;70(6):1100-14
references.pmid: 21689597
references.citation: J Cell Biol. 1999 Feb 8;144(3):519-32
references.pmid: 9971746
references.citation: Clin Genet. 2013 Jan;83(1):53-65
references.pmid: 22283495
references.citation: Hum Mutat. 2013 Dec;34(12):1679-87
references.pmid: 24038936