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Cited by 121Genetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalitiesGenomics and Rare Diseases

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Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

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Gregor, Anne, Albrecht, Beate, Bader, Ingrid, Bijlsma, Emilia K, Ekici, Arif B, Engels, Hartmut, Hackmann, Karl, Horn, Denise, Hoyer, Juliane, Klapecki, Jakub, Kohlhase, Jürgen, Maystadt, Isabelle, Nagl, Sandra, Prott, Eva, Tinschert, Sigrid, Ullmann, Reinhard, Wohlleber, Eva, Woods, Geoffrey, Reis, André, Rauch, Anita, Zweier, Christiane·2011·BMC Medical Genetics
DOI 10.1186/1471-2350-12-106PMC PMC3162517
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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.

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Figure 1 Schematic drawing of NRXN1 with localization of novel and published mutations and deletions. Schematic drawing of genomic structure of alpha 1 isoform of NRXN1 showing domain-coding exons and localization of mutations and deletions. Deletions found in our study are represented by black bars. Published biallelic aberrations are shown with black dotted lines, whereas heterozygous losses and gains are marked by grey solid and dashed lines, respectively. Abbreviations are as follows: SP, signal peptide; LamG, laminin-G domain; EGF, epidermal growth factor like domain; TM, transmembrane region; PDZBD, PDZ-domain binding site.
Figure 1 Schematic drawing of NRXN1 with localization of novel and published mutations and deletions. Schematic drawing of genomic structure of alpha 1 isoform of NRXN1 showing domain-coding exons and localization of mutations and deletions. Deletions found in our study are represented by black bars. Published biallelic aberrations are shown with black dotted lines, whereas heterozygous losses and gains are marked by grey solid and dashed lines, respectively. Abbreviations are as follows: SP, signal peptide; LamG, laminin-G domain; EGF, epidermal growth factor like domain; TM, transmembrane region; PDZBD, PDZ-domain binding site.CC BY · PubMed Central
Figure 2 Schematic drawing of CNTNAP2 with localization of novel and published mutations and deletions. Schematic drawing of genomic structure of CNTNAP2 showing domain-coding exons and localization of mutations and deletions. Mutations and deletions found in our study are represented by black arrows and bars. Published biallelic aberrations are shown with black dotted lines, whereas heterozygous defects are shown in grey. Abbreviations are as follows: SP, signal peptide; DISC, discoidin-like domain; LamG, laminin-G domain; EGF, epidermal growth factor like domain; FIB, fibrinogen-like domain; TM, transmembrane region; PDZBD, PDZ-domain binding site.
Figure 2 Schematic drawing of CNTNAP2 with localization of novel and published mutations and deletions. Schematic drawing of genomic structure of CNTNAP2 showing domain-coding exons and localization of mutations and deletions. Mutations and deletions found in our study are represented by black arrows and bars. Published biallelic aberrations are shown with black dotted lines, whereas heterozygous defects are shown in grey. Abbreviations are as follows: SP, signal peptide; DISC, discoidin-like domain; LamG, laminin-G domain; EGF, epidermal growth factor like domain; FIB, fibrinogen-like domain; TM, transmembrane region; PDZBD, PDZ-domain binding site.CC BY · PubMed Central

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Metadata

Authors
Gregor, A., Albrecht, B., Bader, I., Bijlsma, E. K., Ekici, A. B., Engels, H., Hackmann, K., Horn, D., Hoyer, J., Klapecki, J., Kohlhase, J., Maystadt, I., Nagl, S., Prott, E., Tinschert, S., Ullmann, R., Wohlleber, E., Woods, G., Reis, A., Rauch, A., & Zweier, C.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University of Duisburg-Essen (DE)
  • Leiden University (NL)
  • University of Bonn (DE)
  • Technische Universität Dresden (DE)
  • Charité – Universitätsmedizin Berlin (DE)
  • Instytut Matki i Dziecka (PL)
  • Institute of Pathology and Genetics (BE)
  • Max Planck Institute for Molecular Genetics (DE)
  • Addenbrooke's Hospital (GB)
  • University of Zurich (CH)
Corresponding author
Zweier, Christiane
ORCID
Venue
BMC Medical Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-08-09
Volume
12
Issue
1
Pages
106-106
ISSN
1471-2350 (ISSN-L)
DOI
10.1186/1471-2350-12-106
PMC
PMC3162517
OpenAlex
W2121619206
Cited by
121
References
33
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 12 · 2017: 5 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 20 · 2012: 12
FWCI
9.38
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medical Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • DuEPublico (University of Duisburg-Essen) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
CNTNAP2, NRXN1, severe intellectual disability, heterozygous deletion, recessive inheritance, Pitt-Hopkins syndrome, splice site mutation, frameshift mutation, de novo mutations, second hit, carrier parents, phenotypic variability, neuropsychiatric disorders
MeSH terms
Adolescent, Alleles, Calcium-Binding Proteins, Child, Child Development Disorders, Pervasive, Child, Preschool, Female, Heterozygote, Humans, Hyperventilation, Karyotyping, Male, Membrane Proteins, Intellectual Disability, Nerve Tissue Proteins, Cell Adhesion Molecules, Neuronal, Frameshift Mutation, Gene Deletion, Codon, Terminator, Neural Cell Adhesion Molecules, Facies, RNA Splice Sites, Young Adult

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