Open Access Highly Accessed Research article

Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

Anne Gregor1, Beate Albrecht2, Ingrid Bader3, Emilia K Bijlsma4, Arif B Ekici1, Hartmut Engels5, Karl Hackmann6, Denise Horn7, Juliane Hoyer1, Jakub Klapecki8, Jürgen Kohlhase9, Isabelle Maystadt10, Sandra Nagl11, Eva Prott2, Sigrid Tinschert6, Reinhard Ullmann12, Eva Wohlleber5, Geoffrey Woods13, André Reis1, Anita Rauch14 and Christiane Zweier1*

Author Affiliations

1 Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

2 Institut für Humangenetik, Universitätsklinikum, Universität Duisburg-Essen, Essen, Germany

3 Department of Medical Genetics, Kinderzentrum Munich, Munich, Germany

4 Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands

5 Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany

6 Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

7 Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany

8 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland

9 Center for Human Genetics, Freiburg, Germany

10 Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Gosselies (Charleroi), Belgium

11 Synlab Medizinisches Versorgungszentrum Humane Genetik Munich GmbH, Munich, Germany

12 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany

13 Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK

14 Institute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach, Switzerland

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BMC Medical Genetics 2011, 12:106  doi:10.1186/1471-2350-12-106

Published: 9 August 2011



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.


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.


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.


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.