Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

BMC Medical Genetics

Research Article

Geoffrey Woods¹  Jürgen Kohlhase²  Isabelle Maystadt³  Emilia K Bijlsma⁴  Reinhard Ullmann⁵  Jakub Klapecki⁶  Ingrid Bader⁷  Beate Albrecht⁸  Eva Prott⁸  Karl Hackmann⁹  Sigrid Tinschert⁹  Arif B Ekici^1,10  André Reis^1,10  Christiane Zweier^1,10  Anne Gregor^1,10  Juliane Hoyer^1,10  Hartmut Engels^1,11  Eva Wohlleber^1,11  Denise Horn^1,12  Anita Rauch^1,13  Sandra Nagl^1,14 

[1] Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK;Center for Human Genetics, Freiburg, Germany;Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Gosselies (Charleroi), Belgium;Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands;Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany;Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland;Department of Medical Genetics, Kinderzentrum Munich, Munich, Germany;Institut für Humangenetik, Universitätsklinikum, Universität Duisburg-Essen, Essen, Germany;Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany;Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany;Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany;Institute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach, Switzerland;Synlab Medizinisches Versorgungszentrum Humane Genetik Munich GmbH, Munich, Germany;

关键词: Autism Spectrum Disorder;    Intellectual Disability;    Multiplex Ligation Dependent Probe Amplification;    Truncate Mutation;    Heterozygous Deletion;   

DOI  :  10.1186/1471-2350-12-106

 received in 2011-05-17, accepted in 2011-08-09,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundHeterozygous 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.Methods99 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.ResultsBy 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.ConclusionsWe 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.

【 授权许可】

Unknown   
© Gregor et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.