Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.3 | {Schizophrenia, susceptibility to, 17} | 614332 | 3 | NRXN1 | 600565 |
A number sign (#) is used with this entry because the chromosome 2p16.3 deletion syndrome is associated with a heterozygous contiguous gene deletion that usually includes disruption of the NRXN1 gene (600565).
Susceptibility to schizophrenia-17 (SZCD17) can be caused by variation in the NRXN1 gene.
Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility to autism, schizophrenia (SCZD17), developmental delay, intellectual disability, and dysmorphic features. The phenotype is highly variable and shows incomplete penetrance (summary by Dabell et al., 2013).
For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.
Dabell et al. (2013) identified 34 probands with heterozygous deletions of chromosome 2p16.3 involving exons of the NRXN1 gene from a large cohort of 30,065 samples submitted for oligonucleotide-based array covering the NRXN1 gene who were referred for intellectual disability, developmental delay, and/or multiple congenital anomalies. Clinical features were available for 27 patients who had different deletions ranging in size from 40 to 586 kb. The vast majority of the deletions affected the NRXN1-alpha isoforms. There was wide phenotypic variability, but at least 4 features were shared by the majority of patients: developmental delay, speech delay, abnormal behavior including autism spectrum disorder, and some degree of dysmorphism. In addition, 16% of patients had seizures, and heart and skeletal anomalies were sometimes observed. Eight parents of these patients also carried the deletion, some of whom showed neurocognitive defects and some of whom were normal, indicating incomplete penetrance. The frequency of 2p16.3 deletions in the probands (0.11%) was significantly higher than that observed in controls (0.02%) (p = 6.08 x 10(-7)).
Susceptibility to Autism and Mental Retardation Syndromes
Kim et al. (2008) implicated the NRXN1 gene (600565) in 2 unrelated subjects who displayed an autism spectrum disorder in association with a balanced chromosomal abnormality involving chromosome 2p16.3. In one of the subjects, NRXN1 was disrupted within intron 5. The father possessed the same chromosomal abnormality in the absence of autism, indicating that the interpretation was not fully penetrant and must interact with other factors to produce autism. The breakpoint in the second subject occurred approximately 750 kb 5-prime to NRXN1 within a 2.6-Mb genomic segment that contained no annotated genes. A scan of the NRXN1 coding sequence in a cohort of autistic subjects, relative to non-autistic controls, revealed that amino acid alterations in neurexin-1 are not present at high frequency in autism. However, a number of rare sequence variants in the coding region, including 2 missense changes in conserved residues of the NRXN1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggested that even subtle changes in NRXN1 might contribute to susceptibility to autism.
Using microarray analysis, Schaaf et al. (2012) identified heterozygous intragenic deletions of the NRXN1 gene in 20 (0.25%) of 8,051 patients referred for intellectual disability, autism spectrum disorder, or seizures. Two additional cases with intragenic NRXN1 deletions were also ascertained. The deletions ranged in size from 17 to 913 kb, deleting between 2 and 13 exons. None of the breakpoints were recurrent, except in sibs. Seven individuals had intronic deletions, which were of uncertain significance. The 17 patients with exonic deletions showed a wide range of phenotypes, including delayed psychomotor development/intellectual disability (93%), infantile hypotonia (59%), autism spectrum disorders (56%), and seizures (53%). Attention deficit-hyperactivity disorder was also commonly observed. Congenital malformations and dysmorphic features were not consistent. Three deletions occurred de novo, and 9 were inherited from a parent. Eight (89%) of the 9 parents from whom a deletion was inherited had a history of learning disabilities and/or neuropsychiatric disease. Deletions of the C-terminal region were associated with increased head size and a high frequency of seizure disorders compared to N-terminal deletions.
Susceptibility to Schizophrenia 17
In 1 of 93 individuals with schizophrenia screened by array comparative genomic hybridization (CGH), Kirov et al. (2008) identified a heterozygous 250-kb deletion on chromosome 2p16.3 spanning the promoter and first exon of the NRXN1 gene. The deletion was not found in 372 controls, but was present in an affected sib and their unaffected mother. However, although the mother did not present to psychiatry, she was described as 'odd and neurotic' by the psychiatrist treating her children, suggesting that she may have had subclinical features of the disorder, such as a schizotypal personality.
By array CGH of 150 individuals with schizophrenia and 268 controls, Walsh et al. (2008) identified a heterozygous 115-kb deletion on chromosome 2p16.3 disrupting the NRXN1 gene in a pair of identical twins monozygotic for childhood-onset schizophrenia.
By microarray analysis to screen the NRXN1, NRXN2 (600566), and NRXN3 (600567) genes for copy number variants (CNV) in 2,977 European patients with schizophrenia and 33,746 European controls, Rujescu et al. (2009) identified 66 deletions and 5 duplications in the NRXN1 gene: 12 deletions and 2 duplications occurred in schizophrenia patients (0.47%) compared to 49 and 3 (0.15%) in controls. The CNVs, which varied from 18 to 420 kb, occurred throughout the gene and there was no common breakpoint. No CNVs were found in the NRXN2 or NRXN3 genes. By restricting the association analysis to CNVs that disrupted exons, they identified a significant association with a high odds ratio (p = 0.0027; OR, 8.97; 0.24% cases vs 0.015% controls). Rujescu et al. (2009) suggested that NRXN1 deletions affecting exons may confer risk of schizophrenia.
In a Hungarian woman with the disorganized type of schizophrenia, Gauthier et al. (2011) identified a heterozygous de novo mutation in the NRXN1 gene (600565.0003). In vitro expression studies in COS-7 cells and cultured hippocampal cells showed that the mutant NRXN1 protein was not expressed at the cell surface and was retained in the cytoplasm. Functional studies using rodent cDNA showed that the mutant protein failed to bind partners important in synaptic transmission and showed no synaptogenic activity in a neuronal culture assay. The findings were consistent with a loss of function and haploinsufficiency for the NRXN1 allele.
Dabell, M. P., Rosenfeld, J. A., Bader, P., Escobar, L. F., El-Khechen, D., Vallee, S. E., Dinulos, M. B. P., Curry, C., Fisher, J., Tervo, R., Hannibal, M. C., Siefkas, K., and 21 others. Investigation of NRXN1 deletions: clinical and molecular characterization. Am. J. Med. Genet. 161A: 717-731, 2013. [PubMed: 23495017] [Full Text: https://doi.org/10.1002/ajmg.a.35780]
Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafreniere, R. G., Fathalli, F., Joober, R., and 9 others. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum. Genet. 130: 563-573, 2011. [PubMed: 21424692] [Full Text: https://doi.org/10.1007/s00439-011-0975-z]
Kim, H.-G., Kishikawa, S., Higgins, A. W., Seong, I.-S., Donovan, D. J., Shen, Y., Lally, E., Weiss, L. A., Najm, J., Kutsche, K., Descartes, M., Holt, L., and 14 others. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82: 199-207, 2008. [PubMed: 18179900] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.011]
Kirov, G., Gumus, D., Chen, W., Norton, N., Georuieva, L., Sari, M., O'Donovan, M. C., Erdogan, F., Owen, M. J., Ropers, H. H., Ullmann, R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Molec. Genet. 17: 458-465, 2008. [PubMed: 17989066] [Full Text: https://doi.org/10.1093/hmg/ddm323]
Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., and 41 others. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Molec. Genet. 18: 988-996, 2009. [PubMed: 18945720] [Full Text: https://doi.org/10.1093/hmg/ddn351]
Schaaf, C. P., Boone, P. M., Sampath, S., Williams, C., Bader, P. I., Mueller, J. M., Shchelochkov, O. A., Brown, C. W., Crawford, H. P., Phalen, J. A., Tartaglia, N. R., Evans, P., and 12 others. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Europ. J. Hum. Genet. 20: 1240-1247, 2012. [PubMed: 22617343] [Full Text: https://doi.org/10.1038/ejhg.2012.95]
Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S. M., Rippey, C. F., and 24 others. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539-543, 2008. [PubMed: 18369103] [Full Text: https://doi.org/10.1126/science.1155174]