Abstract
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.
Highlights
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
Recent data suggested that heterozygous variants or defects in NRXN1(Neurexin 1) or CNTNAP2, both genes encoding neuronal cell adhesion molecules, represent susceptibility factors for a broad spectrum of neuropsychiatric disorders such as epilepsy, schizophrenia or autism spectrum disorder (ASD) with reduced penetrance and no or rather mild
To further delineate the clinical phenotype associated with potentially recessive defects in any of the two genes, we screened a group of patients with either severe intellectual disability resembling Pitt-Hopkins syndrome or the phenotypes caused by recessive CNTNAP2 or NRXN1 defects
Summary
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. Recent data suggested that heterozygous variants or defects in NRXN1(Neurexin 1) or CNTNAP2 (contactin associated protein 2), both genes encoding neuronal cell adhesion molecules, represent susceptibility factors for a broad spectrum of neuropsychiatric disorders such as epilepsy, schizophrenia or autism spectrum disorder (ASD) with reduced penetrance and no or rather mild epilepsy [26], resembling Pitt-Hopkins syndrome (PTHS, MIM #610954). To further delineate the clinical phenotype associated with potentially recessive defects in any of the two genes, we screened a group of patients with either severe intellectual disability resembling Pitt-Hopkins syndrome or the phenotypes caused by recessive CNTNAP2 or NRXN1 defects. We performed mutational testing in patients found to harbor heterozygous deletions in either gene
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