title: Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.
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.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chelsea
authors.identifier: 0000-0001-6723-1899
authors.initials: C
authors.lastname: Lowther
authors.affiliation: Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
authors.forename: Marsha
authors.initials: M
authors.lastname: Speevak
authors.affiliation: Regional Genetics Program, Children's Hospital of Eastern Ontario, Toronto, ON, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Armour
authors.affiliation: Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Goh
authors.affiliation: Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Graham
authors.affiliation: Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.|McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
authors.forename: Chumei
authors.initials: C
authors.lastname: Li
authors.affiliation: McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Zeesman
authors.affiliation: 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.
authors.forename: Malgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.affiliation: McMaster Children's Hospital, Department of Pediatrics and Clinical Genetics Program, Hamilton, Ontario, Canada.
authors.forename: Lee-Anne
authors.identifier: 0000-0003-2825-9762
authors.initials: LA
authors.lastname: Schultz
authors.affiliation: Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
authors.forename: Antonella
authors.identifier: 0000-0003-2375-4393
authors.initials: A
authors.lastname: Morra
authors.affiliation: Department of Psychiatry, Western University, London, Ontario, Canada.
authors.forename: Rob
authors.identifier: 0000-0001-7086-7038
authors.initials: R
authors.lastname: Nicolson
authors.affiliation: William Osler Health Centre, Brampton, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Bikangaga
authors.affiliation: Hotel Dieu Hospital, Child Development Centre, Kingston, Ontario, Canada.
authors.forename: Dawa
authors.initials: D
authors.lastname: Samdup
authors.affiliation: Trillium Health Partners Credit Valley Site, Toronto, Ontario, Canada.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Zaazou
authors.affiliation: Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kerry
authors.initials: K
authors.lastname: Boyd
authors.affiliation: London Health Sciences Centre, Children's Hospital of Western Ontario, London, Ontario, Canada.
authors.forename: Jack H
authors.identifier: 0000-0001-8499-5727
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Siu
authors.affiliation: Cambridge Memorial Hospital, Cambridge, Ontario, Canada.
authors.forename: Manjulata
authors.initials: M
authors.lastname: Rajguru
authors.affiliation: Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
authors.forename: Sharan
authors.identifier: 0000-0001-8807-4714
authors.initials: S
authors.lastname: Goobie
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark A
authors.identifier: 0000-0003-0312-3746
authors.initials: MA
authors.lastname: Tarnopolsky
authors.affiliation: Department of Pediatrics, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
authors.forename: Chitra
authors.identifier: 0000-0001-6007-7251
authors.initials: C
authors.lastname: Prasad
authors.affiliation: Grey Bruce Health Services, Owen Sound, Ontario, Canada.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Dick
authors.affiliation: London Health Sciences Centre, Children's Hospital of Western Ontario, London, Ontario, Canada.
authors.forename: Asmaa S
authors.initials: AS
authors.lastname: Hussain
authors.affiliation: Vanboeijen, Assen, The Netherlands.
authors.forename: Margreet
authors.identifier: 0000-0003-3045-4233
authors.initials: M
authors.lastname: Walinga
authors.affiliation: Ipse de Bruggen, Zwammerdam, The Netherlands.
authors.forename: Renske G
authors.identifier: 0000-0002-3667-7721
authors.initials: RG
authors.lastname: Reijenga
authors.affiliation: The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gazzellone
authors.affiliation: The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.affiliation: The Centre for Applied Genomics, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCready
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anne S
authors.identifier: 0000-0003-0099-9945
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D065886:Neurodevelopmental Disorders / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D019683:Penetrance; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules