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Rare Deletions at the Neurexin 3 Locus in Autism Spectrum Disorder

2011; Elsevier BV; Volume: 90; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2011.11.025

ISSN

1537-6605

Autores

Andrea K. Vaags, Anath C. Lionel, Daisuke Sato, McKinsey L. Goodenberger, Quinn Stein, Sarah Curran, Caroline Mackie Ogilvie, Joo Wook Ahn, Irene Drmic, Lili Senman, Christina Chrysler, Ann Thompson, Carolyn Russell, Aparna Prasad, Susan Walker, Dalila Pinto, Christian R. Marshall, Dimitri J. Stavropoulos, Lonnie Zwaigenbaum, Bridget A. Fernandez, Éric Fombonne, Patrick Bolton, David Collier, Jennelle C. Hodge, Wendy Roberts, Peter Szatmari, Stephen W. Scherer,

Tópico(s)

Genetics and Neurodevelopmental Disorders

Resumo

The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses. The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses. Incremental progress has been made in elucidating genetic factors involved in autism spectrum disorder (ASD [MIM 209850]). Most notably, researchers have identified both rare inherited and de novo copy-number variants (CNVs) and have subsequently performed sequence-based validation.1Szatmari P. Paterson A.D. Zwaigenbaum L. Roberts W. Brian J. Liu X.Q. Vincent J.B. Skaug J.L. Thompson A.P. Senman L. et al.Autism Genome Project ConsortiumMapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat. Genet. 2007; 39: 319-328Crossref PubMed Scopus (1095) Google Scholar, 2Sebat J. Lakshmi B. Malhotra D. Troge J. Lese-Martin C. Walsh T. Yamrom B. Yoon S. Krasnitz A. Kendall J. et al.Strong association of de novo copy number mutations with autism.Science. 2007; 316: 445-449Crossref PubMed Scopus (2011) Google Scholar, 3Marshall C.R. Noor A. Vincent J.B. Lionel A.C. Feuk L. Skaug J. Shago M. Moessner R. Pinto D. Ren Y. et al.Structural variation of chromosomes in autism spectrum disorder.Am. J. Hum. Genet. 2008; 82: 477-488Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 4Glessner J.T. Wang K. Cai G. Korvatska O. Kim C.E. Wood S. Zhang H. Estes A. Brune C.W. Bradfield J.P. et al.Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009; 459: 569-573Crossref PubMed Scopus (991) Google Scholar, 5Pinto D. Pagnamenta A.T. Klei L. Anney R. Merico D. Regan R. Conroy J. Magalhaes T.R. Correia C. Abrahams B.S. et al.Functional impact of global rare copy number variation in autism spectrum disorders.Nature. 2010; 466: 368-372Crossref PubMed Scopus (1424) Google Scholar, 6Sanders S.J. Ercan-Sencicek A.G. Hus V. Luo R. Murtha M.T. Moreno-De-Luca D. Chu S.H. Moreau M.P. Gupta A.R. Thomson S.A. et al.Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.Neuron. 2011; 70: 863-885Abstract Full Text Full Text PDF PubMed Scopus (888) Google Scholar, 7Levy D. Ronemus M. Yamrom B. Lee Y.H. Leotta A. Kendall J. Marks S. Lakshmi B. Pai D. Ye K. et al.Rare de novo and transmitted copy-number variation in autistic spectrum disorders.Neuron. 2011; 70: 886-897Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 8Cook Jr., E.H. Scherer S.W. Copy-number variations associated with neuropsychiatric conditions.Nature. 2008; 455: 919-923Crossref PubMed Scopus (480) Google Scholar, 9Scherer S.W. Dawson G. Risk factors for autism: translating genomic discoveries into diagnostics.Hum. Genet. 2011; 130: 123-148Crossref PubMed Scopus (87) Google Scholar NRXN1,1Szatmari P. Paterson A.D. Zwaigenbaum L. Roberts W. Brian J. Liu X.Q. Vincent J.B. Skaug J.L. Thompson A.P. Senman L. et al.Autism Genome Project ConsortiumMapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat. Genet. 2007; 39: 319-328Crossref PubMed Scopus (1095) Google Scholar NLGN3,10Jamain S. Quach H. Betancur C. Råstam M. Colineaux C. Gillberg I.C. Soderstrom H. Giros B. Leboyer M. Gillberg C. Bourgeron T. Paris Autism Research International Sibpair StudyMutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.Nat. Genet. 2003; 34: 27-29Crossref PubMed Scopus (1306) Google Scholar NLGN4,10Jamain S. Quach H. Betancur C. Råstam M. Colineaux C. Gillberg I.C. Soderstrom H. Giros B. Leboyer M. Gillberg C. Bourgeron T. Paris Autism Research International Sibpair StudyMutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.Nat. Genet. 2003; 34: 27-29Crossref PubMed Scopus (1306) Google Scholar SHANK3,11Durand C.M. Betancur C. Boeckers T.M. Bockmann J. Chaste P. Fauchereau F. Nygren G. Rastam M. Gillberg I.C. Anckarsäter H. et al.Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.Nat. Genet. 2007; 39: 25-27Crossref PubMed Scopus (1069) Google Scholar, 12Moessner R. Marshall C.R. Sutcliffe J.S. Skaug J. Pinto D. Vincent J. Zwaigenbaum L. Fernandez B. Roberts W. Szatmari P. Scherer S.W. Contribution of SHANK3 mutations to autism spectrum disorder.Am. J. Hum. Genet. 2007; 81: 1289-1297Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar and SHANK213Berkel S. Marshall C.R. Weiss B. Howe J. Roeth R. Moog U. Endris V. Roberts W. Szatmari P. Pinto D. et al.Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.Nat. Genet. 2010; 42: 489-491Crossref PubMed Scopus (379) Google Scholar and genomic regions at 1q21.1,1Szatmari P. Paterson A.D. Zwaigenbaum L. Roberts W. Brian J. Liu X.Q. Vincent J.B. Skaug J.L. Thompson A.P. Senman L. et al.Autism Genome Project ConsortiumMapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat. Genet. 2007; 39: 319-328Crossref PubMed Scopus (1095) Google Scholar 16p11.2,3Marshall C.R. Noor A. Vincent J.B. Lionel A.C. Feuk L. Skaug J. Shago M. Moessner R. Pinto D. Ren Y. et al.Structural variation of chromosomes in autism spectrum disorder.Am. J. Hum. Genet. 2008; 82: 477-488Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 14Weiss L.A. Shen Y. Korn J.M. Arking D.E. Miller D.T. Fossdal R. Saemundsen E. Stefansson H. Ferreira M.A. Green T. et al.Autism ConsortiumAssociation between microdeletion and microduplication at 16p11.2 and autism.N. Engl. J. Med. 2008; 358: 667-675Crossref PubMed Scopus (1218) Google Scholar DDX53-PTCHD1,3Marshall C.R. Noor A. Vincent J.B. Lionel A.C. Feuk L. Skaug J. Shago M. Moessner R. Pinto D. Ren Y. et al.Structural variation of chromosomes in autism spectrum disorder.Am. J. Hum. Genet. 2008; 82: 477-488Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 5Pinto D. Pagnamenta A.T. Klei L. Anney R. Merico D. Regan R. Conroy J. Magalhaes T.R. Correia C. Abrahams B.S. et al.Functional impact of global rare copy number variation in autism spectrum disorders.Nature. 2010; 466: 368-372Crossref PubMed Scopus (1424) Google Scholar, 15Noor A. Whibley A. Marshall C.R. Gianakopoulos P.J. Piton A. Carson A.R. Orlic-Milacic M. Lionel A.C. Sato D. Pinto D. et al.Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.Sci Transl Med. 2010; 2: 49ra68Crossref PubMed Scopus (140) Google Scholar and others9Scherer S.W. Dawson G. Risk factors for autism: translating genomic discoveries into diagnostics.Hum. Genet. 2011; 130: 123-148Crossref PubMed Scopus (87) Google Scholar are all bona fide ASD risk loci. Rare exonic deletions within NRXN1 (MIM 600565) at 2p16.3 are among the most consistently observed findings from CNV investigations of ASD. After the initial report of 300 kb hemizygous de novo lesions that eliminated several NRXN1 exons in two female siblings with ASD,1Szatmari P. Paterson A.D. Zwaigenbaum L. Roberts W. Brian J. Liu X.Q. Vincent J.B. Skaug J.L. Thompson A.P. Senman L. et al.Autism Genome Project ConsortiumMapping autism risk loci using genetic linkage and chromosomal rearrangements.Nat. Genet. 2007; 39: 319-328Crossref PubMed Scopus (1095) Google Scholar several other studies have also detected deletions at this locus in ASD.4Glessner J.T. Wang K. Cai G. Korvatska O. Kim C.E. Wood S. Zhang H. Estes A. Brune C.W. Bradfield J.P. et al.Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009; 459: 569-573Crossref PubMed Scopus (991) Google Scholar, 5Pinto D. Pagnamenta A.T. Klei L. Anney R. Merico D. Regan R. Conroy J. Magalhaes T.R. Correia C. Abrahams B.S. et al.Functional impact of global rare copy number variation in autism spectrum disorders.Nature. 2010; 466: 368-372Crossref PubMed Scopus (1424) Google Scholar, 6Sanders S.J. Ercan-Sencicek A.G. Hus V. Luo R. Murtha M.T. Moreno-De-Luca D. Chu S.H. Moreau M.P. Gupta A.R. Thomson S.A. et al.Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.Neuron. 2011; 70: 863-885Abstract Full Text Full Text PDF PubMed Scopus (888) Google Scholar, 7Levy D. Ronemus M. Yamrom B. Lee Y.H. Leotta A. Kendall J. Marks S. Lakshmi B. Pai D. Ye K. et al.Rare de novo and transmitted copy-number variation in autistic spectrum disorders.Neuron. 2011; 70: 886-897Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 16Shen Y. Dies K.A. Holm I.A. Bridgemohan C. Sobeih M.M. Caronna E.B. Miller K.J. Frazier J.A. Silverstein I. Picker J. et al.Autism Consortium Clinical Genetics/DNA Diagnostics CollaborationClinical genetic testing for patients with autism spectrum disorders.Pediatrics. 2010; 125: e727-e735Crossref PubMed Scopus (266) Google Scholar, 17Guilmatre A. Dubourg C. Mosca A.L. Legallic S. Goldenberg A. Drouin-Garraud V. Layet V. Rosier A. Briault S. Bonnet-Brilhault F. et al.Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.Arch. Gen. Psychiatry. 2009; 66: 947-956Crossref PubMed Scopus (335) Google Scholar, 18Bremer A. Giacobini M. Eriksson M. Gustavsson P. Nordin V. Fernell E. Gillberg C. Nordgren A. Uppströmer A. Anderlid B.M. et al.Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2011; 156: 115-124Crossref PubMed Scopus (54) Google Scholar, 19Ching M.S. Shen Y. Tan W.H. Jeste S.S. Morrow E.M. Chen X. Mukaddes N.M. Yoo S.Y. Hanson E. Hundley R. et al.Children's Hospital Boston Genotype Phenotype Study GroupDeletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2010; 153B: 937-947PubMed Google Scholar, 20Kim H.G. Kishikawa S. Higgins A.W. Seong I.S. Donovan D.J. Shen Y. Lally E. Weiss L.A. Najm J. Kutsche K. et al.Disruption of neurexin 1 associated with autism spectrum disorder.Am. J. Hum. Genet. 2008; 82: 199-207Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar Exonic NRXN1 deletions, which are extremely rare in controls,19Ching M.S. Shen Y. Tan W.H. Jeste S.S. Morrow E.M. Chen X. Mukaddes N.M. Yoo S.Y. Hanson E. Hundley R. et al.Children's Hospital Boston Genotype Phenotype Study GroupDeletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2010; 153B: 937-947PubMed Google Scholar have also been reported in cases with schizophrenia,17Guilmatre A. Dubourg C. Mosca A.L. Legallic S. Goldenberg A. Drouin-Garraud V. Layet V. Rosier A. Briault S. Bonnet-Brilhault F. et al.Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.Arch. Gen. Psychiatry. 2009; 66: 947-956Crossref PubMed Scopus (335) Google Scholar, 21International Schizophrenia ConsortiumRare chromosomal deletions and duplications increase risk of schizophrenia.Nature. 2008; 455: 237-241Crossref PubMed Scopus (1232) Google Scholar, 22Walsh T. McClellan J.M. McCarthy S.E. Addington A.M. Pierce S.B. Cooper G.M. Nord A.S. Kusenda M. Malhotra D. Bhandari A. et al.Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.Science. 2008; 320: 539-543Crossref PubMed Scopus (1395) Google Scholar, 23Kirov G. Gumus D. Chen W. Norton N. Georgieva L. Sari M. O'Donovan M.C. Erdogan F. Owen M.J. Ropers H.H. Ullmann R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.Hum. Mol. Genet. 2008; 17: 458-465Crossref PubMed Scopus (314) Google Scholar, 24Kirov G. Grozeva D. Norton N. Ivanov D. Mantripragada K.K. Holmans P. Craddock N. Owen M.J. O'Donovan M.C. International Schizophrenia ConsortiumWellcome Trust Case Control ConsortiumSupport for the involvement of large copy number variants in the pathogenesis of schizophrenia.Hum. Mol. Genet. 2009; 18: 1497-1503Crossref PubMed Scopus (327) Google Scholar, 25Vrijenhoek T. Buizer-Voskamp J.E. van der Stelt I. Strengman E. Sabatti C. Geurts van Kessel A. Brunner H.G. Ophoff R.A. Veltman J.A. Genetic Risk and Outcome in Psychosis (GROUP) ConsortiumRecurrent CNVs disrupt three candidate genes in schizophrenia patients.Am. J. Hum. Genet. 2008; 83: 504-510Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 26Rujescu D. Ingason A. Cichon S. Pietiläinen O.P. Barnes M.R. Toulopoulou T. Picchioni M. Vassos E. Ettinger U. Bramon E. et al.GROUP InvestigatorsDisruption of the neurexin 1 gene is associated with schizophrenia.Hum. Mol. Genet. 2009; 18: 988-996Crossref PubMed Scopus (367) Google Scholar intellectual disability,17Guilmatre A. Dubourg C. Mosca A.L. Legallic S. Goldenberg A. Drouin-Garraud V. Layet V. Rosier A. Briault S. Bonnet-Brilhault F. et al.Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.Arch. Gen. Psychiatry. 2009; 66: 947-956Crossref PubMed Scopus (335) Google Scholar, 19Ching M.S. Shen Y. Tan W.H. Jeste S.S. Morrow E.M. Chen X. Mukaddes N.M. Yoo S.Y. Hanson E. Hundley R. et al.Children's Hospital Boston Genotype Phenotype Study GroupDeletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2010; 153B: 937-947PubMed Google Scholar, 27Friedman J.M. Baross A. Delaney A.D. Ally A. Arbour L. Armstrong L. Asano J. Bailey D.K. Barber S. Birch P. et al.Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.Am. J. Hum. Genet. 2006; 79: 500-513Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar bipolar disorder,28Zhang D. Cheng L. Qian Y. Alliey-Rodriguez N. Kelsoe J.R. Greenwood T. Nievergelt C. Barrett T.B. McKinney R. Schork N. et al.Singleton deletions throughout the genome increase risk of bipolar disorder.Mol. Psychiatry. 2009; 14: 376-380Crossref PubMed Scopus (119) Google Scholar attention deficit hyperactivity disorder (ADHD),29Bradley W.E. Raelson J.V. Dubois D.Y. Godin E. Fournier H. Privé C. Allard R. Pinchuk V. Lapalme M. Paulussen R.J. Belouchi A. Hotspots of large rare deletions in the human genome.PLoS ONE. 2010; 5: e9401Crossref PubMed Scopus (43) Google Scholar Tourette syndrome,30Sundaram S.K. Huq A.M. Wilson B.J. Chugani H.T. Tourette syndrome is associated with recurrent exonic copy number variants.Neurology. 2010; 74: 1583-1590Crossref PubMed Scopus (90) Google Scholar and autosomal-recessive Pitt-Hopkins syndrome.31Zweier C. de Jong E.K. Zweier M. Orrico A. Ousager L.B. Collins A.L. Bijlsma E.K. Oortveld M.A. Ekici A.B. Reis A. et al.CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila.Am. J. Hum. Genet. 2009; 85: 655-666Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar These reports, taken together with findings of cognitive impairments, aberrant synaptic electrophysiology, and behavioral changes in Nrxn1-knockout mice,32Etherton M.R. Blaiss C.A. Powell C.M. Südhof T.C. Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.Proc. Natl. Acad. Sci. USA. 2009; 106: 17998-18003Crossref PubMed Scopus (301) Google Scholar provide strong evidence for the involvement of NRXN1 in the etiology of ASD and other neurodevelopmental disorders. There is also a report of a truncating mutation in NRXN2 (MIM 600566) in an ASD case.33Gauthier J. Siddiqui T.J. Huashan P. Yokomaku D. Hamdan F.F. Champagne N. Lapointe M. Spiegelman D. Noreau A. Lafrenière R.G. et al.Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.Hum. Genet. 2011; 130: 563-573Crossref PubMed Scopus (191) Google Scholar The human neurexin gene family includes three unlinked genes (NRXN1, NRXN2, and NRXN3 [MIM 600567]), each of which encodes alpha and beta isoforms.34Südhof T.C. Neuroligins and neurexins link synaptic function to cognitive disease.Nature. 2008; 455: 903-911Crossref PubMed Scopus (1197) Google Scholar The neurexins are highly expressed in presynaptic terminals and have been shown to have important roles in synaptic cell adhesion and neurotransmitter secretion.35Missler M. Zhang W. Rohlmann A. Kattenstroth G. Hammer R.E. Gottmann K. Südhof T.C. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis.Nature. 2003; 423: 939-948Crossref PubMed Scopus (483) Google Scholar Here, we describe the pedigrees (Figure 1), detailed phenotypes (Table 1), and genotypes (Figure 2 and Tables S1, S2, and S4–S7, available online) of ASD cases with rare deletions at 14q24.3-31.1, which overlaps NRXN3.Table 1Summary of Clinical Characteristics for Individuals with NRXN3 DeletionsPatient ID and KaryotypeNRXN3 Deletion CoordinatesaNCBI 36 (hg18). and Deleted Exon(s)Clinical DetailsDxAxOtherF1-003 (proband)46,XY14q24.3(77,933,816–77,996,755)exon 1 (alpha)Asperger syndrome (ADI-R and clinical Dx)Age: 16 yr, 7 months; IQ: Leiter-R IQ= 119 (92%); Language: OWLS: RL = 121 (92%) and EL = DTC; Adaptive Behavior: VABS-I: ABC = 75(5%), COM = 96 (39%), DLS = 94 (34%), and SOC = 52 (<1%)aggression, anger, anxiety, transition and stimulation (photo-, phono-, and osmophobia) difficulties, sleeplessness, depression, and headachesF1-005 (sister)47,XX,+2114q24.3(77,933,816–77,996,755)exon 1 (alpha)Down syndrome (karyotype and clinical Dx)First Ax. Age: 11 yr, 4 months: ADOS-2 = ASD; ADI-R = Non-ASD (except behavior); did not meet clinical criteria (by developmental pediatrician); no ASD Dx; IQ: Leiter-R IQ = 46 (<1%); Language: OWLS: TL = 40 (<1%), RL = < 40 (<1%), and EL = 43 (<1%); Adaptive Behavior: VABS-I: ABC = 49 (<1%), DLS = 46 (<1%), and SOC = 64 (1%)born at 34 weeks, heart defect, sleep apnea, ear infections, fatigue, fear and anxiety, obsessive behavior, impulsive behavior, and difficulties with transitions, attention, and emotional regulationSecond Ax. Age: 16 yr: ADOS-3 and ADI-R, met criteria for BEV and COM, but not for SD; did not meet clinical criteria (by developmental pediatrician and psychologist); no ASD Dx; IQ: WASI: FSIQ = 51 (<1%), VIQ = 55 (<1%), PIQ = 54 (<1%); Language: OWLS: TL = 40 (<1%), RL = 40 (<1%), EL = 40 (<1%)F1-001 (mother)46,XX14q24.3(77,933,816–77,996,755)exon 1 (alpha)nonehigh energy, social difficulties, anxiety, and auditory and language-processing difficultiesF2-003 (proband)46,XY14q31.1(79,194,918–79,486,635)exons 14-17 (alpha) and 3–7 (beta)autism (ADI-R and ADOS-1)Age: 3 yr, 5 months; IQ: Leiter-R IQ = INC; Language: OWLS: INC; PPVT-4: SS = 67 (<1%); Adaptive Behavior: VABS-II: ABC = 61 (<1%), COM = 63 (1%), DLS = 60 (<1%), SOC = 59 (<1%), and MOT = 72 (3%)born at 31 weeks, asthma, and juvenile arthritisF2-004 (sister)46,XX14q31.1(79,194,918–79,486,635)exons 14-17 (alpha) and 3–7 (beta)autism (ADI-R and ADOS-1)Age: 3 yr, 9 months; IQ: Leiter-R IQ = 82 (12%); Language: OWLS: INC; PPVT: INC; Adaptive Behavior: VABS-II: ABC = 60 (<1%), COM = 54 (<1%), DLS = 64 (1%), SOC = 57 (<1%), and MOT = 75 (5%)born at 31 weeks, asthma, and nonabsent seizuresF2-001 (father)46,XY14q31.1(79,194,918–79,486,635) exons 14-17 (alpha) and 3–7 (beta)noneAlexithymia: TAS-20 = 41 (not alexithymic)color blindF3-003 (proband)46,XY14q31.1(∼78,503,451–78,839,469)exons 10-12 (alpha) and 1 (beta)autism (ADI-R)Age: 13 yr; IQ: WASI: FSIQ = 71 (3%)aggression, self harm, obsessive behavior, suicidal and homicidal thoughts, delusional and persecutory ideas, sleep issues, and obesityF3-001 (father)46,XY14q31.1(∼78,503,451–78,839,469)exons 10-12 (alpha) and 1 (beta)BAP (clinical Dx)social avoidance, depression, aggression, alcoholism, obsessive behavior, compulsive behavior, illiteracy, asthma, and emphysemaF4-003 (proband)46,XY14q31.1 (∼78,766,127–79,013,263)exon 13 (alpha) and 1–2 (beta)autism (clinical Dx, C-TRF, DSM)Age: 3 yr, 6 months; IQ: Leiter-R IQ = INCaggression, anger, anxiety, temper tantrums, social avoidance, sucking and biting of hands and fingers, sleep-onset disorder, upper-body hypotonia, thumb-flexion difficulty, oppositional defiance, previous head banging, and prior speech delayAbbreviations are as follows: Dx, diagnosis; Ax, assessment; COM, communication; SD, social deficit; TL, total language; RL, receptive language; EL, expressive language; DTC, declined to complete; ABC, adaptive behavior composite; DLS, daily living skills; SOC, socialization; INC, incomplete (test was attempted but subject failed to complete); MOT, motor skills; SS, standardized score; WASI, Wechsler Abbreviated Scale of Intelligence; FSIQ, full scale IQ; VIQ, verbal IQ; and PIQ, performance IQ. See text for remaining abbreviations.a NCBI 36 (hg18). Open table in a new tab Figure 2Extent of Genomic NRXN3 Deletions at Chromosomal Region 14q24.3-q31.1Show full captionDeletions are shown in red. CNVs detected in control populations (described in this paper) and from the Database of Genomic Variants55Zhang J. Feuk L. Duggan G.E. Khaja R. Scherer S.W. Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome.Cytogenet. Genome Res. 2006; 115: 205-214Crossref PubMed Scopus (167) Google Scholar, 56Iafrate A.J. Feuk L. Rivera M.N. Listewnik M.L. Donahoe P.K. Qi Y. Scherer S.W. Lee C. Detection of large-scale variation in the human genome.Nat. Genet. 2004; 36: 949-951Crossref PubMed Scopus (2250) Google Scholar are also shown. Genomic coordinates and isoform information are from hg18. Control data are as described in this paper.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Abbreviations are as follows: Dx, diagnosis; Ax, assessment; COM, communication; SD, social deficit; TL, total language; RL, receptive language; EL, expressive language; DTC, declined to complete; ABC, adaptive behavior composite; DLS, daily living skills; SOC, socialization; INC, incomplete (test was attempted but subject failed to complete); MOT, motor skills; SS, standardized score; WASI, Wechsler Abbreviated Scale of Intelligence; FSIQ, full scale IQ; VIQ, verbal IQ; and PIQ, performance IQ. See text for remaining abbreviations. Deletions are shown in red. CNVs detected in control populations (described in this paper) and from the Database of Genomic Variants55Zhang J. Feuk L. Duggan G.E. Khaja R. Scherer S.W. Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome.Cytogenet. Genome Res. 2006; 115: 205-214Crossref PubMed Scopus (167) Google Scholar, 56Iafrate A.J. Feuk L. Rivera M.N. Listewnik M.L. Donahoe P.K. Qi Y. Scherer S.W. Lee C. Detection of large-scale variation in the human genome.Nat. Genet. 2004; 36: 949-951Crossref PubMed Scopus (2250) Google Scholar are also shown. Genomic coordinates and isoform information are from hg18. Control data are as described in this paper. Initially, to assess the presence of CNVs in a research cohort of 1,158 Canadian individuals with ASD, we genotyped DNA with Affymetrix GeneChip SNP 6.0 (family 1 proband [F1-003] and family 2 sister [F2-004]), Illumina Infinium 1M single SNP (F1-003 and family 2 proband, F2-003), Illumina Omni 2.5M (family 1 sister, F1-005), and/or Agilent Human comparative genomic hybridization (CGH) 1M (F2-003) microarrays. These studies were approved by the Hospital for Sick Children (Toronto) research ethics board, and informed consent was obtained. We analyzed CNVs by using published methods,5Pinto D. Pagnamenta A.T. Klei L. Anney R. Merico D. Regan R. Conroy J. Magalhaes T.R. Correia C. Abrahams B.S. et al.Functional impact of global rare copy number variation in autism spectrum disorders.Nature. 2010; 466: 368-372Crossref PubMed Scopus (1424) Google Scholar, 36Lionel A.C. Crosbie J. Barbosa N. Goodale T. Thiruvahindrapuram B. Rickaby J. Gazzellone M. Carson A.R. Howe J.L. Wang Z. et al.Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.Sci Transl Med. 2011; 3: 95ra75Crossref PubMed Scopus (248) Google Scholar, 37Pinto D. Darvishi K. Shi X. Rajan D. Rigler D. Fitzgerald T. Lionel A.C. Thiruvahindrapuram B. Macdonald J.R. Mills R. et al.Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants.Nat. Biotechnol. 2011; 29: 512-520Crossref PubMed Scopus (310) Google Scholar and we classified them as described.38Tsuchiya K.D. Shaffer L.G. Aradhya S. Gastier-Foster J.M. Patel A. Rudd M.K. Biggerstaff J.S. Sanger W.G. Schwartz S. Tepperberg J.H. et al.Variability in interpreting and reporting copy number changes detected by array-based technology in clinical laboratories.Genet. Med. 2009; 11: 866-873Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar To ascertain the prevalence of NRXN3 CNVs, we examined the NRXN3 region in published data from 2,026 healthy individuals from the Children's Hospital of Philadelphia,39Shaikh T.H. Gai X. Perin J.C. Glessner J.T. Xie H. Murphy K. O'Hara R. Casalunovo T. Conlin L.K. D'Arcy M. et al.High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications.Genome Res. 2009; 19: 1682-1690Crossref PubMed Scopus (293) Google Scholar from 2,493 controls genotyped at the University of Washington40Itsara A. Cooper G.M. Baker C. Girirajan S. Li J. Absher D. Krauss R.M. Myers R.M. Ridker P.M. Chasman D.I. et al.Population analysis of large copy number variants and hotspots of human genetic disease.Am. J. Hum. Genet. 2009; 84: 148-161Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar and in microarray data that our group analyzed from 10,603 population-based controls.3Marshall C.R. Noor A. Vincent J.B. Lionel A.C. Feuk L. Skaug J. Shago M. Moessner R. Pinto D. Ren Y. et al.Structural variation of chromosomes in autism spectrum disorder.Am. J. Hum. Genet. 2008; 82: 477-488Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 5Pinto D. Pagnamenta A.T. Klei L. Anney R. Merico D. Regan R. Conroy J. Magalhaes T.R. Correia C. Abrahams B.S. et al.Functional impact of global rare copy number variation in autism spectrum disorders.Nature. 2010; 466: 368-372Crossref PubMed Scopus (1424) Google Scholar, 15Noor A. Whibley A. Marshall C.R. Gianakopoulos P.J. Piton A. Carson A.R. Orlic-Milacic M. Lionel A.C. Sato D. Pinto D. et al.Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.Sci Transl Med. 2010; 2: 49ra68Crossref PubMed Scopus (140) Google Scholar, 36Lionel A.C. Crosbie J. Barbosa N. Goodale T. Thiruvahindrapuram B. Rickaby J. Gazzellone M. Carson A.R. Howe J.L. Wang Z. et al.Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.Sci Transl Med. 2011; 3: 95ra75Crossref PubMed Scopus (248) Google Scholar This latter dataset included 1,123 controls from northern Germany,41Krawczak M. Nikolaus S. von Eberstein H. Croucher P.J. El Mokhtari N.E. Schreiber S. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships.Community Genet. 2006; 9: 55-61Crossref PubMed Scopus (265) Google Scholar 1,234 controls from Ottawa42Stewart A.F. Dandona S. Chen L. Assogba O. Belanger M. Ewart G. LaRose R. Doelle H. Williams K. Wells G.A. et al.Kinesin family member 6 variant Trp719Arg does not associate with angiographically defined coronary artery disease in the Ottawa Heart Genomics Study.J. Am. Coll. Cardi

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