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PMID: 27195815 Published · ppublish English Journal Article

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.

Genetics in medicine : official journal of the American College of Medical Genetics ·Vol. 19 ·No. 1 ·2017-00-00 ·Pages 53-61

Lowther C, Speevak M, Armour CM, Goh ES, Graham GE, Li C, Zeesman S, Nowaczyk MJ, Schultz LA, Morra A, Nicolson R, Bikangaga P, Samdup D, Zaazou M, Boyd K, Jung JH, Siu V, Rajguru M, Goobie S, Tarnopolsky MA, Prasad C, Dick PT, Hussain AS, Walinga M, Reijenga RG, Gazzellone M, Lionel AC, Marshall CR, Scherer SW, Stavropoulos DJ, McCready E, Bassett AS

Abstract

The purpose of the current study was to assess the penetrance of NRXN1 deletions. We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). The results support the importance of exons near the 5' end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61.

MeSH Terms
Calcium-Binding Proteins Cell Adhesion Molecules, Neuronal/genetics Child DNA Copy Number Variations Exons/genetics Female Genetic Predisposition to Disease Genotype Humans Introns/genetics Male Microarray Analysis Nerve Tissue Proteins/genetics Neural Cell Adhesion Molecules Neurodevelopmental Disorders/epidemiology,genetics,physiopathology Penetrance Phenotype Sequence Deletion
Chemicals
Calcium-Binding Proteins Cell Adhesion Molecules, Neuronal NRXN1 protein, human Nerve Tissue Proteins Neural Cell Adhesion Molecules
Authors & Affiliations
32 authors, click to expand affiliations / ORCID
Lowther Chelsea ORCID
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Speevak Marsha
Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
Armour Christine M
Regional Genetics Program, Children's Hospital of Eastern Ontario, Toronto, ON, Canada.
Goh Elaine S
Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
Graham Gail E
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
Li Chumei
Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada. | McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
Zeesman Susan
McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
Nowaczyk Malgorzata J M
McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada. | Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Schultz Lee-Anne ORCID
McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
Morra Antonella ORCID
Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
Nicolson Rob ORCID
Department of Psychiatry, Western University, London, Ontario, Canada.
Bikangaga Peter
William Osler Health Centre, Brampton, Ontario, Canada.
Samdup Dawa
Hotel Dieu Hospital, Child Development Centre, Kingston, Ontario, Canada.
Zaazou Mostafa
Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
Boyd Kerry
Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
Jung Jack H ORCID
London Health Sciences Centre, Children's Hospital of Western Ontario, London, Ontario, Canada.
Siu Victoria
Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
Rajguru Manjulata
Cambridge Memorial Hospital, Cambridge, Ontario, Canada.
Goobie Sharan ORCID
Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
Tarnopolsky Mark A ORCID
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Prasad Chitra ORCID
Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
Dick Paul T
Grey Bruce Health Services, Owen Sound, Ontario, Canada.
Hussain Asmaa S
London Health Sciences Centre, Children's Hospital of Western Ontario, London, Ontario, Canada.
Walinga Margreet ORCID
Vanboeijen, Assen, The Netherlands.
Reijenga Renske G ORCID
Ipse de Bruggen, Zwammerdam, The Netherlands.
Gazzellone Matthew
The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
Lionel Anath C
The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
Marshall Christian R
The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
Scherer Stephen W
The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada. | McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Stavropoulos Dimitri J
Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada.
McCready Elizabeth
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Bassett Anne S ORCID
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. | Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
References (38)
38 references, click to expand
  1. Investigation of NRXN1 deletions: clinical and molecular characterization.
    Am J Med Genet A. 2013 Apr;161A(4):717-31 PMID: 23495017
  2. Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes.
    Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):303-13 PMID: 24700553
  3. Mechanisms of Long Non-coding RNAs in Mammalian Nervous System Development, Plasticity, Disease, and Evolution.
    Neuron. 2015 Dec 2;88(5):861-77 PMID: 26637795
  4. miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome.
    Front Genet. 2012 Dec 13;3:291 PMID: 23248646
  5. Conserved domain structure of beta-neurexins. Unusual cleaved signal sequences in receptor-like neuronal cell-surface proteins.
    J Biol Chem. 1994 Apr 22;269(16):11987-92 PMID: 8163501
  6. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants.
    Genet Med. 2011 Jul;13(7):680-5 PMID: 21681106
  7. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.
    Eur J Hum Genet. 2012 Dec;20(12):1240-7 PMID: 22617343
  8. Phenotypic heterogeneity of genomic disorders and rare copy-number variants.
    N Engl J Med. 2012 Oct 4;367(14):1321-31 PMID: 22970919
  9. The expression and alternative splicing of alpha-neurexins during Xenopus development.
    Int J Dev Biol. 2006;50(1):39-46 PMID: 16323076
  10. Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
    Nat Genet. 2007 Mar;39(3):319-28 PMID: 17322880
  11. Identification of candidate intergenic risk loci in autism spectrum disorder.
    BMC Genomics. 2013 Jul 24;14:499 PMID: 23879678
  12. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins.
    Neuron. 2005 Oct 20;48(2):229-36 PMID: 16242404
  13. Structural variation of chromosomes in autism spectrum disorder.
    Am J Hum Genet. 2008 Feb;82(2):477-88 PMID: 18252227
  14. Splice form dependence of beta-neurexin/neuroligin binding interactions.
    Neuron. 2010 Jul 15;67(1):61-74 PMID: 20624592
  15. NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series - further understanding of the relevance of NRXN1 to neurodevelopmental disorders.
    J Mol Psychiatry. 2013 Apr 23;1(1):4 PMID: 25408897
  16. Disruption of the neurexin 1 gene is associated with schizophrenia.
    Hum Mol Genet. 2009 Mar 1;18(5):988-96 PMID: 18945720
  17. Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.
    Sci Transl Med. 2010 Sep 15;2(49):49ra68 PMID: 20844286
  18. Diagnostic utility of microarray testing in pregnancy loss.
    Ultrasound Obstet Gynecol. 2015 Oct;46(4):478-86 PMID: 25846569
  19. LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development.
    J Neurosci. 2010 Jun 2;30(22):7495-506 PMID: 20519524
  20. ChIP-chip analysis of neurexins and other candidate genes for addiction and neuropsychiatric disorders.
    J Neurogenet. 2010 Mar;24(1):5-17 PMID: 19968605
  21. Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.
    J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):910-9 PMID: 25062598
  22. Two rare deletions upstream of the NRXN1 gene (2p16.3) affecting the non-coding mRNA AK127244 segregate with diverse psychopathological phenotypes in a family.
    Eur J Med Genet. 2015 Dec;58(12 ):650-3 PMID: 26563496
  23. Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.
    Am J Med Genet B Neuropsychiatr Genet. 2013 Jun;162B(4):388-403 PMID: 23533028
  24. VISTA Enhancer Browser--a database of tissue-specific human enhancers.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D88-92 PMID: 17130149
  25. Neurexins are differentially expressed in the embryonic nervous system of mice.
    J Neurosci. 1995 Apr;15(4):2849-56 PMID: 7722633
  26. Prenatal-screening companies expand scope of DNA tests.
    Nature. 2014 Mar 6;507(7490):19 PMID: 24598619
  27. A stoichiometric complex of neurexins and dystroglycan in brain.
    J Cell Biol. 2001 Jul 23;154(2):435-45 PMID: 11470830
  28. A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.
    J Med Genet. 2008 Apr;45(4):239-43 PMID: 18057082
  29. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.
    Nat Genet. 2014 Jul;46(7):742-7 PMID: 24859339
  30. Increased Rate of Sporadic and Recurrent Rare Genic Copy Number Variants in Parkinson's Disease Among Ashkenazi Jews.
    Mol Genet Genomic Med. 2013 Sep;1(3):142-154 PMID: 24073418
  31. Analysis of copy number variation in Alzheimer's disease: the NIALOAD/ NCRAD Family Study.
    Curr Alzheimer Res. 2012 Sep;9(7):801-14 PMID: 22486522
  32. Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.
    Cell. 2010 Jun 11;141(6):1068-79 PMID: 20537373
  33. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.
    Sci Transl Med. 2011 Aug 10;3(95):95ra75 PMID: 21832240
  34. CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.
    PLoS One. 2013;8(3):e59061 PMID: 23533600
  35. A copy number variation map of the human genome.
    Nat Rev Genet. 2015 Mar;16(3):172-83 PMID: 25645873
  36. The Database of Genomic Variants: a curated collection of structural variation in the human genome.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D986-92 PMID: 24174537
  37. Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing.
    Genomics. 2002 Jun;79(6):849-59 PMID: 12036300
  38. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.
    Epilepsia. 2013 Feb;54(2):256-64 PMID: 23294455
Article Info
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
Abbr.
Genet Med
ISSN
1530-0366
DOI
10.1038/gim.2016.54
Published
2017-00-00
Epub
2016-00-19
Pages
53-61
Language
English
Region
United States
NLM ID
9815831
PMCID
PMC4980119
Subset
IM
Grants
Canadian Institutes of Health Research · 103582-1 · Canada
Canadian Institutes of Health Research · 111238-1 · Canada
Canadian Institutes of Health Research · 89066-1 · Canada
External Links
PubMed source DOI: 10.1038/gim.2016.54 PMC Full Text View journal details
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