title: Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.
abstract: BACKGROUND
  Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability.
  
  
  METHODS
  99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced.
  
  
  RESULTS
  By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation.
  
  
  CONCLUSIONS
  We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gregor
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bader
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoyer
authors.forename: Jakub
authors.initials: J
authors.lastname: Klapecki
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.forename: Sandra
authors.initials: S
authors.lastname: Nagl
authors.forename: Eva
authors.initials: E
authors.lastname: Prott
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Eva
authors.initials: E
authors.lastname: Wohlleber
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Woods
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
mesh_terms: D000293:Adolescent; D000483:Alleles; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D002675:Child, Preschool; D018388:Codon, Terminator; D019066:Facies; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D006985:Hyperventilation / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D022821:RNA Splice Sites; D055815:Young Adult
chemical_list: C403049:CNTNAP2 protein, human; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018388:Codon, Terminator; D008565:Membrane Proteins; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D022821:RNA Splice Sites