title: Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.
abstract: BACKGROUND
  Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.
  
  
  METHODS
  Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.
  
  
  RESULTS
  We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.
  
  
  CONCLUSIONS
  These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Tabet
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; INSERM, UMR 1141, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Pilorge
authors.affiliation: INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Delaby
authors.affiliation: Department of Child and Adolescent Psychiatry, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; Fondation Fondamental, 40 rue de Mesly, 94000 Créteil, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Kungsgatan 12, 41119 Göteborg, Sweden.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nygren
authors.affiliation: Département de Génétique et Procréation, CHU de Grenoble, Hôpital Couple-Enfant, avenue du Maquis du Grésivaudan, 38043 Grenoble, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Devillard
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gérard
authors.affiliation: INSERM, UMR 1141, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; Neurology Unit, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.affiliation: Medical Genetics Unit, AP-HP, Pitié-Salpêtrière University Hospital, 47 boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Service de Génétique et d'Embryologie Médicales, AP-HP, Trousseau Hospital, 26 avenue du Docteur Arnold Netter, 75012 Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.affiliation: Medical Genetics Unit, AP-HP, Pitié-Salpêtrière University Hospital, 47 boulevard de l'Hôpital, 75013 Paris, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Jacquette
authors.affiliation: INSERM, UMR 1141, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; Cytogenetics Unit, AP-HP, Jean Verdier Hospital, allée du 14 Juillet, 93140 Bondy, France ; Paris 13 University, Sorbonne Paris Cité, UFR SMBH, 74 rue Marcel Cachin, 93000 Bobigny, France.
authors.forename: Andrée
authors.initials: A
authors.lastname: Delahaye
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Perrin
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dupont
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France.
authors.forename: Azzedine
authors.initials: A
authors.lastname: Aboura
authors.affiliation: Medical Genetics Unit, AP-HP, Jean Verdier Hospital, allée du 14 Juillet, 93140 Bondy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.affiliation: Foundation for Autism Research, 3081 Quail Hollow, Sarasota, FL 34235 USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Coleman
authors.affiliation: Fondation Fondamental, 40 rue de Mesly, 94000 Créteil, France ; Department of Psychiatry, AP-HP, Henri Mondor-Albert Chenevier Hospital, 40 rue de Mesly, 94000 Créteil, France ; INSERM U955, Institut Mondor de Recherche Biomédicale, Psychiatric Genetics, 8 rue du Général Sarrail, 94000 Créteil, France ; Faculty of Medicine, University Paris-Est Créteil, 8 rue du Général Sarrail, 94000 Créteil, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Kungsgatan 12, 41119 Göteborg, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; INSERM, UMR 1141, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; Cytogenetics Unit, AP-HP, Jean Verdier Hospital, allée du 14 Juillet, 93140 Bondy, France ; Paris 13 University, Sorbonne Paris Cité, UFR SMBH, 74 rue Marcel Cachin, 93000 Bobigny, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Benzacken
authors.affiliation: INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
references.citation: J Med Genet. 2007 Dec;44(12):750-62
references.pmid: 17766364
references.citation: Eur J Med Genet. 2009 Sep-Oct;52(5):291-6
references.pmid: 19505601
references.citation: Brain Res. 2011 Mar 22;1380:42-77
references.pmid: 21129364
references.citation: Am J Hum Genet. 2014 May 1;94(5):677-94
references.pmid: 24768552
references.citation: Ann Genet. 1986;29(3):129-68
references.pmid: 3538996
references.citation: Am J Med Genet A. 2006 Jun 1;140(11):1164-71
references.pmid: 16691587
references.citation: Am J Hum Genet. 1991 Nov;49(5):995-1013
references.pmid: 1928105
references.citation: Am J Med Genet A. 2011 Apr;155A(4):819-24
references.pmid: 21412978
references.citation: Eur J Med Genet. 2010 Sep-Oct;53(5):227-33
references.pmid: 20542150
references.citation: Am J Hum Genet. 2008 Apr;82(4):927-36
references.pmid: 18371933
references.citation: J Med Genet. 2006 Jun;43(6):478-89
references.pmid: 16199540
references.citation: Am J Med Genet A. 2009 Jun;149A(6):1302-7
references.pmid: 19449429
references.citation: Am J Med Genet. 2001 Jul 22;102(1):76-80
references.pmid: 11471177
references.citation: Eur J Hum Genet. 2013 Jun;21(6):602-12
references.pmid: 23073310
references.citation: PLoS Genet. 2012;8(3):e1002606
references.pmid: 22479201
references.citation: Curr Opin Genet Dev. 2013 Jun;23(3):310-5
references.pmid: 23537858
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):219-28
references.pmid: 20691407
references.citation: Genet Med. 2011 Jul;13(7):680-5
references.pmid: 21681106
references.citation: J Med Genet. 1992 Feb;29(2):103-8
references.pmid: 1613759
references.citation: Cell. 2012 Apr 27;149(3):525-37
references.pmid: 22521361
references.citation: Ann Genet. 1992;35(1):51-4
references.pmid: 1610121
references.citation: Am J Med Genet A. 2011 Mar;155A(3):656-9
references.pmid: 21351245
references.citation: Am J Med Genet C Semin Med Genet. 2010 Nov 15;154C(4):417-26
references.pmid: 20981770
references.citation: Pediatrics. 2010 Apr;125(4):e727-35
references.pmid: 20231187
references.citation: J Med Genet. 2004 Jun;41(6):433-9
references.pmid: 15173228
references.citation: Am J Med Genet A. 2011 Sep;155A(9):2224-8
references.pmid: 21815251
references.citation: Eur J Hum Genet. 2011 Nov;19(11):1152-60
references.pmid: 21712853
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Hum Genet. 2008 Jul;123(6):607-16
references.pmid: 18470537
references.citation: Prenat Diagn. 2005 Jun;25(6):451-5
references.pmid: 15966060
references.citation: Am J Med Genet A. 2010 Jan;152A(1):196-202
references.pmid: 20034085
references.citation: Am J Med Genet. 1987 Jan;26(1):95-101
references.pmid: 3812584
references.citation: J Med Genet. 2013 Mar;50(3):144-50
references.pmid: 23315544
references.citation: BMC Med Genet. 2005 May 17;6:21
references.pmid: 15904506
references.citation: Am J Med Genet A. 2013 Sep;161A(9):2358-62
references.pmid: 23894085
references.citation: Cytogenet Genome Res. 2009;125(2):103-8
references.pmid: 19729912
references.citation: Am J Med Genet A. 2010 Sep;152A(9):2346-54
references.pmid: 20684015
references.citation: Eur J Neurosci. 2006 Aug;24(4):1020-30
references.pmid: 16930429
references.citation: Genet Med. 2011 Oct;13(10):868-80
references.pmid: 21792059
references.citation: Eur J Pediatr. 1995 Jun;154(6):425-31
references.pmid: 7671938
references.citation: Autism Res. 2009 Oct;2(5):258-66
references.pmid: 19877165
references.citation: Cytogenet Genome Res. 2010;129(4):265-74
references.pmid: 20606397
references.citation: Mol Cytogenet. 2008 Jul 21;1:15
references.pmid: 18644119
references.citation: Am J Hum Genet. 2008 Mar;82(3):712-22
references.pmid: 18319076
references.citation: Am J Med Genet A. 2010 Jul;152A(7):1781-8
references.pmid: 20583184
references.citation: Mol Cell Neurosci. 2009 Dec;42(4):466-83
references.pmid: 19796685
references.citation: Genet Med. 2008 Aug;10(8):599-611
references.pmid: 18641517
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):484-91
references.pmid: 17427195
references.citation: Autism. 2004 Mar;8(1):49-60
references.pmid: 15070547
references.citation: Am J Med Genet A. 2004 Oct 15;130A(3):299-302
references.pmid: 15378535
references.citation: J Med Genet. 2009 Oct;46(10):694-702
references.pmid: 19293169
references.citation: J Med Genet. 2005 Jan;42(1):8-16
references.pmid: 15635069
references.citation: J Med Genet. 2004 Sep;41(9):691-8
references.pmid: 15342700
references.citation: Psychiatr Genet. 2008 Jun;18(3):101-9
references.pmid: 18496206
references.citation: Clin Genet. 2009 Jun;75(6):505-13
references.pmid: 19508415
references.citation: Am J Med Genet A. 2003 Jul 1;120A(1):123-6
references.pmid: 12794704
references.citation: Eur J Med Genet. 2010 May-Jun;53(3):136-40
references.pmid: 20197130
references.citation: Biol Psychiatry. 2009 Aug 15;66(4):349-59
references.pmid: 19278672
references.citation: Mol Cell Biol. 2004 May;24(10 ):4417-27
references.pmid: 15121860