Year: 2011
Type: article
Study design: Observational Study
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.
Source: BMC Medical Genetics
Authors: Anne Gregor, Beate Albrecht, Ingrid Bader, Emilia K Bijlsma, Arif B Ekici, Hartmut Engels, Karl Hackmann, Denise Horn, Juliane Hoyer, Jakub Klapecki, Jürgen Kohlhase, Isabelle Maystadt, Sandra Nagl, Eva Prott, Sigrid Tinschert, Reinhard Ullmann, Eva Wohlleber, Geoffrey Woods, André Reis, Anita Rauch, Christiane Zweier
Institutions: Friedrich-Alexander-Universität Erlangen-Nürnberg, University of Duisburg-Essen, Leiden University, Leiden University Medical Center, University of Bonn, Technische Universität Dresden, Charité – Universitätsmedizin Berlin, Instytut Matki i Dziecka, Institute of Pathology and Genetics, Max Planck Institute for Molecular Genetics, Addenbrooke's Hospital, Wellcome Trust, University of Zurich
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,380
OpenAlex ID: W2121619206