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  Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

Gregor, A., Albrecht, B., Bader, I., Bijlsma, E. K., Ekici, A. B., Engels, H., et al. (2011). Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet, 12, 106. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21827697 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162517/pdf/1471-2350-12-106.pdf?tool=pmcentrez.

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Gregor, A., Author
Albrecht, B., Author
Bader, I., Author
Bijlsma, E. K., Author
Ekici, A. B., Author
Engels, H., Author
Hackmann, K., Author
Horn, D., Author
Hoyer, J., Author
Klapecki, J., Author
Kohlhase, J., Author
Maystadt, I., Author
Nagl, S., Author
Prott, E., Author
Tinschert, S.1, Author              
Ullmann, R.2, Author              
Wohlleber, E., Author
Woods, G., Author
Reis, A., Author
Rauch, A., Author
Zweier, C., Author more..
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              


Free keywords: Adolescent; Alleles; Cell Adhesion Molecules, Neuronal/*genetics; Child; Child Development Disorders, Pervasive/genetics; Child, Preschool; Codon, Terminator; Facies; Female; Frameshift Mutation; Gene Deletion; Heterozygote; Humans; Hyperventilation/genetics; Intellectual Disability/*genetics; Karyotyping; Male; Membrane Proteins/*genetics; Nerve Tissue Proteins/*genetics; RNA Splice Sites; Young Adult
 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.


 Dates: 2011
 Publication Status: Published in print
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Title: BMC Med Genet
Source Genre: Journal
Publ. Info: -
Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: 106 Identifier: ISSN: 1471-2350 (Electronic) 1471-2350 (Linking)