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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.

Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1