Entry - *604569 - CONTACTIN-ASSOCIATED PROTEIN-LIKE 2; CNTNAP2 - OMIM - (OMIM.ORG)

 
 
* 604569

CONTACTIN-ASSOCIATED PROTEIN-LIKE 2; CNTNAP2


Alternative titles; symbols

CONTACTIN-ASSOCIATED PROTEIN 2; CASPR2
NEUREXIN IV, DROSOPHILA, HOMOLOG OF; NRXN4


HGNC Approved Gene Symbol: CNTNAP2

Cytogenetic location: 7q35-q36.1   Genomic coordinates (GRCh38) : 7:146,116,801-148,420,998 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
7q35-q36.1 {Autism susceptibility 15} 612100 3
Pitt-Hopkins like syndrome 1 610042 AR 3

TEXT

▼ Description

The CNTNAP2 gene encodes a neuronal transmembrane protein member of the neurexin superfamily involved in neural-glia interactions and clustering of potassium channels in myelinated axons. Rapid conduction in myelinated axons depends on the generation of specialized subcellular domains to which different sets of ion channels are localized. Contactin-associated protein (CNTNAP1; 602346) is another member of the neurexin superfamily (summary by Poliak et al., 1999).


▼ Cloning and Expression

By searching sequence databases for homologs of CASPR, Poliak et al. (1999) identified several CASPR-related ESTs from various nervous system sources. They used 1 of these ESTs to isolate human brain and spinal cord cDNAs representing the entire CASPR2 coding sequence. The structural organization of the deduced 1,333-amino acid CASPR2 protein is very similar to that of CASPR and the related Drosophila Nrx IV, all having the hallmarks of type I transmembrane proteins. The extracellular region of CASPR2 is a mosaic of domains, including discoidin/neuropilin- and fibrinogen-like domains, 2 epidermal growth factor (EGF; 131530) repeats, and 4 domains similar to a region in laminin A (150320), referred to as the G domain. The extracellular region of CASPR2 also contains 12 potential N-linked glycosylation sites. CASPR2 has a short C-terminal region containing a binding site for type II PDZ domains. CASPR2 shares 45% amino acid sequence identity with CASPR and 34% identity with Drosophila Nrx IV. Recombinant CASPR2 expressed in mammalian cells had an apparent molecular mass of 180 kD. Northern blot analysis of human tissues detected 9- and 10-kb CASPR2 transcripts in brain, but only the 9-kb transcript in spinal cord. Low levels of CASPR2 mRNA were also detected in the ovary and prostate. The authors determined the expression pattern of CASPR2 within the adult human central nervous system. Like the spinal cord, the corpus callosum expressed only the 9-kb CASPR2 transcript. The 9-kb transcript was also the predominant transcript in the medulla, substantia nigra, and caudate nucleus. All the other regions examined, namely cerebellum, cortex, occipital pole, frontal lobe, temporal lobe, putamen, amygdala, hippocampus, subthalamic nucleus, and thalamus, expressed similar levels of the 9- and 10-kb CASPR2 transcripts. Immunolocalization of Caspr2 in adult rat brain demonstrated that Caspr2 is differentially expressed in distinct neuronal structures, including the soma and dendrites, and in specific short-segmented pairs along myelinated axons. Caspr2 expression in myelinated nerves was mostly confined to the axon at the juxtaparanodal region and to some isolated paranodal loops. In the juxtaparanodal region, Caspr2 precisely colocalized with Shaker-like potassium channels. Caspr2 specifically associated with Kv1.1 (176260), Kv1.2 (176262), and their Kv-beta-2 subunit (601142). This association involved the C-terminal region of Caspr2. Poliak et al. (1999) suggested that CASPR2 may stabilize the localization of potassium channels in the juxtaparanodal region, and that CASPR2 family members may play a role in the local differentiation of the axon into distinct functional subdomains.

Krumbiegel et al. (2011) performed comprehensive mRNA and protein expression analysis in ocular tissues from eyes with PEX syndrome/glaucoma (177650) and normal and glaucomatous control eyes. Quantitative real-time PCR showed ubiquitous expression of CNTNAP2 in virtually all ocular tissues with no significant difference between PEXS and control tissues. By immunohistochemistry, CNTNAP2 could be localized mainly to the cell membranes of epithelial and endothelial cells, the corneal endothelium, trabecular endothelial cells and endothelial cells lining the Schlemm canal, and iris pigment epithelium as well as the ciliary epithelium of both PEXS and control eyes. CNTNAP2 was also found to be expressed by vascular endothelial and smooth muscle cells, for example, in the conjunctival stroma, iris stroma, and choroidal stroma. In the retina, a marked labeling of retinal ganglion cells and retinal nerve fibers was present. Moreover, positive staining of the nerve fibers and glial cells was observed in the retrolaminar portion of the optic nerve. Electron microscopy with immunogold labeling confirmed a distinct reaction of cell membranes with CNTNAP2 antibodies, for example, in the basal membrane infoldings of nonpigmented ciliary epithelial cells. Krumbiegel et al. (2011) observed that in PEXS tissues, immunogold labeling of cell membranes appeared to be reduced close to cellular surface compartments from which the PEXS fibrils appeared to emerge.


▼ Gene Structure

Alarcon et al. (2008) detected 24 exons in the CNTNAP2 gene.


▼ Mapping

Poliak et al. (1999) noted that the CNTNAP2 gene had been mapped to chromosome 7q35-q36, between D7S688 and D7S505, using an STS.


▼ Gene Function

Abrahams et al. (2007) used 2 sets of microarray analyses followed by selective in situ hybridization to identify differentially expressed genes in the superior temporal gyrus and cerebral cortex in midgestation human fetal brains. CNTNAP2 was consistently expressed at high levels in the prefrontal and anterior temporal cortex, as well as in the dorsal thalamus, caudate, putamen, and amygdala. In contrast to the findings in humans, Cntnap2 was broadly expressed in the developing rodent brain. Abrahams et al. (2007) noted that human CNTNAP2 expression was enriched in circuits involved in higher cortical functions, including language.

Vernes et al. (2008) found that the transcription factor FOXP2 (605317) directly regulates expression of CNTNAP2 by binding to a regulatory sequence in intron 1. Expression analysis of developing human cortex at 18 to 22 weeks' gestation showed complementary patterns of expression of FOXP2 and CNTNAP2 with respect to cortical lamination: CNTNAP2 expression was lowest in layers that showed highest levels of FOXP2. Vernes et al. (2008) identified CNTNAP2 polymorphisms with significant quantitative associations with nonsense-word repetition (see SLI4, 612514). The region containing these polymorphisms coincides with one associated with language delays in children with autism, as described by Arking et al. (2008). Mutations in the FOXP2 gene cause a monogenic speech and language disorder (602081). Vernes et al. (2008) concluded that by integrating functional genomics and quantitative trait analyses, they identified a shared neurogenetic pathway that is disturbed in specific forms of language impairment.


▼ Cytogenetics

Verkerk et al. (2003) reported a family in which the father had obsessive-compulsive disorder (OCD; 164230) and both of his children, a girl and a boy, had Gilles de la Tourette syndrome (GTS; 137580), OCD, mental retardation, speech abnormalities, and growth retardation. All 3 individuals had a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The father had inv(2)(p23q22),ins(7;2) (q35-q36;p21p23) and the 2 affected children inherited the abnormal chromosome 7, sharing the 2p21-p23 insertion on 7q35-q36. Both children had a normal chromosome 2; thus both children had 3 copies of this region on chromosome 2. Fine mapping of the involved regions using FISH and BAC clones showed that the insertion interrupted the CNTNAP2 gene. Verkerk et al. (2003) hypothesized that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of potassium channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.

Belloso et al. (2007) reported a familial balanced reciprocal translocation t(7;15)(q35;q26.1) in phenotypically normal individuals, in which the 7q35 breakpoint disrupted the CNTNAP2 gene. The authors concluded that truncation of CNTNAP2 does not necessarily result in the Gilles de la Tourette syndrome.

Poot et al. (2010) reported a boy with autism, delayed motor development, mild ataxia with poor coordination, hyperactivity, poor speech development, outbursts, and some features of GTS. The authors described a highly complex chromosomal rearrangement involving at least 3 breaks in chromosome 1 and 7 breaks in chromosome 7 on the paternally derived chromosome. There was a de novo paracentric inversion of chromosome 7q32.1-7q35 that disrupted the CNTNAP2 gene. Additionally, 2 CNTNAP2 gene segments were inserted into a gene-poor region on the chromosome 1q31.2 region. There was also a de novo deletion encompassing the distal part of intron 1 and exon 2 of CNTNAP2, and a de novo deletion of chromosome 1q41, containing 15 annotated genes including KCTD3 (613272) and USH2A (608400), which has been reported as an autism susceptibility locus (AUTS11; 610836). Poot et al. (2010) suggested that haploinsufficiency for the CNTNAP2 gene may have caused the GTS features, and that the combination of CNTNAP2 disruption and 1q41 deletion may have acted together to result in full-blown autism.


▼ Molecular Genetics

Pitt-Hopkins-Like Syndrome 1

Strauss et al. (2006) reported a homozygous mutation in the CNTNAP2 gene in Old Order Amish children with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), which the authors designated CDFE syndrome (cortical dysplasia-focal epilepsy syndrome). Temporal lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2. Four affected children and their 6 parents were used for analysis of SNPs in a microarray analysis. A large block of putative autozygosity was identified on chromosome 7q36. Sequencing of the CNTNAP2 gene revealed a 1-bp deletion (3709delG; 604569.0001), resulting in frameshift and a premature stop codon and predicted to yield a nonfunctional protein, owing to a lack of transmembrane and cytoplasmic domains. Genotype analysis of 105 healthy Old Order Amish controls revealed none who was homozygous for 3709delG but identified 4 carriers. Sequencing of the CNTNAP2 gene in 18 additional Old Order Amish patients with complex partial seizures identified the mutation in 9 additional patients from 7 sibships who had the characteristic clinical features of PTHSL1.

Zweier et al. (2009) identified homozygous or compound heterozygous mutations in the CNTNAP2 gene (604569.0005-604569.0007) in 2 sibs and 1 unrelated child with mental retardation, seizures, and hyperbreathing patterns, reminiscent of Pitt-Hopkins syndrome (see 610954). Dysmorphic features were not prominent. In Drosophila, overexpression of the CNTNAP2 homolog Nrxn4 resulted in increased density of synaptic active zones and reorganization of synaptic morphology, suggesting a role for this protein at the synapse.

In 8 patients from 6 unrelated families with PTHSL1, Smogavec et al. (2016) identified homozygous or compound heterozygous truncating mutations and/or intragenic deletions in the CNTNAP2 gene (see, e.g., 604569.0008-604569.0013). The patients were ascertained from different genetics or pediatric centers worldwide. The mutations and deletions were found by various methods, including microarray analysis, gene panel sequencing, and targeted sequencing. Carrier parents were unaffected, although 1 had anxiety and emotional lability; none underwent psychiatric testing. Functional studies of the variants were not performed, but all were predicted to result in a loss of function.

Susceptibility to Autism

Alarcon et al. (2008), Arking et al. (2008), and Bakkaloglu et al. (2008) identified SNPs in the CNTNAP2 gene (see, e.g., 604569.0002-604569.0004) that were associated with increased susceptibility to autism (AUTS15; 612100). In gene expression analyses in developing human brain, Alarcon et al. (2008) identified CNTNAP2 as enriched in circuits important for language development. By in situ and biochemical analyses, Bakkaloglu et al. (2008) confirmed expression of CNTNAP2 in relevant brain regions and demonstrated the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates.

Exfoliation Syndrome

For discussion of a possible association between variation in the CNTNAP2 gene and exfoliation syndrome, see 177650.

▼ Animal Model

In Drosophila, Zweier et al. (2009) found that knockdown of Nrxn4 ubiquitously or specifically in neurons was embryonic lethal, with embryos failing to hatch. This was associated with decreased staining intensity of the presynaptic protein bruchpilot (nc82) in Nrxn4-knockdown embryos. Overexpression of Nrxn4 was associated with increased bruchpilot staining and changes in the morphologic organization of synapses. Examination of Drosophila larval neuromuscular junctions detected the presence of Nrxn4 at synaptic terminals localized in a pattern of subsynaptic foci that overlapped active zones. The findings of Nxrn4 were similar to that of Nxrn1 (600565), suggesting an overlapping function of these proteins.

Penagarikano et al. (2011) found expression of the Cntnap2 gene in various brain regions of embryonic mice beginning around embryonic day 14. Expression was observed in the ventricular proliferative zones of the developing cortex and ganglionic eminences, where excitatory projection neurons and inhibitory interneurons arise, respectively, and overlapped with regions containing migrating neurons and postmigratory cells, indicating a possible role in neuron development and/or migration. In the adult mouse, Cntnap2 was expressed in multiple brain regions, primarily cerebral cortex, hippocampus, striatum, olfactory tract, and cerebellar cortex. Cntnap2-null mice had no gross morphologic brain changes, but had ectopic neurons in the corpus callosum and deep cortex, reflecting a migration defect. Cntnap1 was found to be expressed in GABAergic inhibitory interneurons in normal mice, and these neurons were reduced in mutant mice. Neuronal firing in mutant mice was asynchronous compared to wildtype, and the mutant mice showed abnormal behavior, including increased locomotor activity, hyperreactivity to thermal sensory stimuli, stereotypic motor movements, and impaired communication and social interactions. These features were reminiscent of autism, and suggested that abnormal neuronal circuit architecture and firing underlie the disorder. Treatment of the mice with risperidone improved the motor behavioral abnormalities and improved nesting deficits, both likely mediated by the corticostriatal dopaminergic circuits, whereas other social behavior was not improved. The findings suggested distinct circuitries involved in these components of autism. Mutant mice also developed seizures at around 6 months of age.

Dawes et al. (2018) found that treatment with human CASPR2 antibodies caused pain-related hypersensitivity in mice. CASPR2 antibodies bound to peripheral nervous system, particularly at the level of dorsal root ganglion (DRG) neurons, but did not cause a gross neuroinflammatory response or damage the nervous system. Similarly, Caspr2 -/- mice displayed pain-related hypersensitivity with no major anatomic or transcriptional changes at the level of the DRG or spinal cord. Caspr2 cell-autonomously regulated excitability of DRG neurons by mediating membrane expression of Kv1 voltage-gated potassium channels. As a result, DRG neurons from Caspr2 -/- mice became hyperresponsive to mechanical and chemical stimuli. In addition, Caspr2 deletion resulted in hyperexcitability to D-hair primary afferents and dorsal horns. In support of these results, treatment of cultured mouse DRG neurons with human CASPR2 antibodies caused loss of membrane expression of Kv1 channels and increased their excitability.


▼ ALLELIC VARIANTS ( 13 Selected Examples):

.0001 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1-BP DEL, 3709G
  
RCV000005825...

In Old Order Amish patients with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Strauss et al. (2006) identified a homozygous 1-bp deletion (3709delG) in exon 22 of the CNTNAP2 gene. The deletion was predicted to cause a frameshift that would result in the misincorporation of 16 amino acids beginning at position 1237. Premature termination of translation would occur at codon 1253. The mutation was predicted to yield a nonfunctional protein owing to the loss of the transmembrane and intracellular domains.


.0002 AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, IVS13, C-T
  
RCV000005826

In a 2-stage analysis of a 10-Mb quantitative trait locus for autism-related traits on 7q35-q36 (AUTS15; 612100) using parent-child trios, Alarcon et al. (2008) identified an association between variation at rs2710102 in the CNTNAP2 gene and age at first word in autism spectrum disorder samples from male-only families (p = 0.005). The authors noted that the SNP association results did not imply that variation at rs2710102 is causally related to autism spectrum disorder, but rather that variation here is likely to be in linkage disequilibrium with an untested functional variant.

A genomewide association study by Ma et al. (2009) of 438 Caucasian families with 1,390 individuals with autism and validation in an additional cohort of 2,390 samples from 457 families did not show a significant association between autism and rs2710102, which was the tagging SNP in the study of Alarcon et al. (2008). No tested markers linking to the CNTNAP2 gene were significant after correction.


.0003 AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, IVS2, A-T (rs7794745)
  
RCV000005827

In 2 independent family-based samples, Arking et al. (2008) identified a common variant in the CNTNAP2 gene, rs7794745, that was associated with increased risk for autism (AUTS15; 612100). This SNP resides in intron 2 of the CNTNAP2 gene. In the combined sample, overall transmission frequency of the T allele to affected children (tau = 0.55, p less than 7.35 x 10(05)) was significantly greater from mothers (tau = 0.61) than from fathers (tau = 0.53), and this parent-of-origin difference was significant (P less than 0.001).


.0004 AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, ILE869THR
  
RCV000005828...

In 4 children with autism (AUTS15; 612100) from 3 unrelated families, Bakkaloglu et al. (2008) identified an ile869-to-thr (I869T) substitution in the CNTNAP2 protein. The mutation occurred at a conserved residue in the third laminin G domain and was predicted to be deleterious. In each family the variant was inherited from an apparently unaffected parent. The variant was not present in 4,010 control chromosomes.


.0005 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1.1-MB DEL, EX2-9
   RCV000005829

In 2 sibs with Pitt-Hopkins-like syndrome-1 (PTHLS1; 610042) reported by Orrico et al. (2001), Zweier et al. (2009) identified a homozygous 1.1-Mb deletion of exons 2 through 9 of the CNTNAP2 gene. The patients had severe mental retardation, hyperbreathing, and seizures.


.0006 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, IVS10AS, G-T, -1
  
RCV000005830...

In a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Zweier et al. (2009) identified compound heterozygosity for 2 mutations in the CNTNAP2 gene: a G-to-T transversion in intron 10 and a 180-kb deletion of exons 5 through 8. The splice site was not identified in 384 controls chromosomes, and was predicted to result in the skipping of exon 10 and cause a frameshift and the loss of 2 laminin G domains. There was no CNTNAP2 expression in blood or fibroblasts. The patient had severe mental retardation with lack of speech, mildly delayed motor development, hyperbreathing, and seizures.


.0007 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 180-KB DEL, EX5-8
   RCV000005831

For discussion of the 180-kb deletion of exons 5 through 8 in the CNTNAP2 gene that was found in compound heterozygous state in a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Zweier et al. (2009), see 604569.0006.


.0008 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, GLU494TER
  
RCV000505263

In a 12.5-year-old girl (patient 1) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified a homozygous c.1480G-T transversion (c.1480G-T, NM_014141) in exon 9 of the CNTNAP2 gene, resulting in a glu494-to-ter (E494X) substitution. The mutation, which was found by targeted sequencing of the CNTNAP2 gene, was heterozygous in both unaffected parents; it was found at a very low frequency (8 x 10(-6)) in the ExAC database in the heterozygous state. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.


.0009 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, EX1 DEL
   RCV000505265

In a 2-year-old girl (patient 2) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified compound heterozygous mutations in the CNTNAP2 gene: the paternal allele carried a deletion of exon 1 (chr7.144,520,633-145,949,971, GRCh37), including loss of the start codon, whereas the maternal allele carried a c.3046C-T transition in exon 19, resulting in an arg1016-to-ter (R1016X; 604569.0010) substitution. The mutations were found by a combination of microarray analysis and direct sequencing; the R1016X mutation was not found in the ExAC database. Functional studies of the variants were not performed, but they were predicted to result in a complete loss of function.


.0010 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, ARG1016TER
  
RCV000505261...

For discussion of the c.3046C-T transition (c.3046C-T, NM_014141) in the CNTNAP2 gene, resulting in an arg1016-to-ter (R1016X) substitution, that was found in compound heterozygous state in a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Smogavec et al. (2016), see 604569.0009.


.0011 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, EX9-10 DEL
   RCV000505264

In 2 adult brothers (patients 4 and 5) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified compound heterozygous mutations in the CNTNAP2 gene: one allele carried a deletion of exons 9 and 10 (chr7.146,988,989-147,101,705, GRCh37), whereas the other carried a 1-bp deletion (c.2963delC; 604569.0012) in exon 18, resulting in a frameshift and premature termination (Cys989AlafsTer45). The parental origin of each mutation was discordant in the figure and table versus the text. The mutations were found by a combination of microarray analysis and genetic analysis of a multigene panel direct sequencing; the 1-bp deletion was not found in the ExAC database. Functional studies of the variants were not performed, but they were predicted to result in a complete loss of function.


.0012 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1-BP DEL, 2963C
  
RCV000505266

For discussion of the 1-bp deletion ( c.2963delC, NM_014141) in the CNTNAP2 gene, resulting in a frameshift and premature termination (Cys989AlafsTer45), that was found in compound heterozygous state in 2 brothers with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Smogavec et al. (2016), see 604569.0011.


.0013 PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, CYS682TER
  
RCV000505262

In 2 brothers (patients 7 and 8) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified a homozygous c.2046C-A transversion (c.2046C-A, NM_014141) in exon 13 of the CNTNAP2 gene, resulting in a cys682-to-ter (C682X) substitution. The mutation, which was found by gene panel sequencing, segregated with the disorder in the family and was not found in the ExAC database. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.


▼ REFERENCES

  1. Abrahams, B. S., Tentler, D., Perederiy, J. V., Oldham, M. C., Coppola, G., Geschwind, D. H. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Nat. Acad. Sci. 104: 17849-17854, 2007. [PubMed: 17978184, images, related citations] [Full Text]

  2. Alarcon, M., Abrahams, B. S., Stone, J. L., Duvall, J. A., Perederiy, J. V., Bomar, J. M., Sebat, J., Wigler, M., Martin, C. L., Ledbetter, D. H., Nelson, S. F., Cantor, R. M., Geschwind, D. H. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82: 150-159, 2008. [PubMed: 18179893, images, related citations] [Full Text]

  3. Arking, D. E., Cutler, D. J., Brune, C. W., Teslovich, T. M., West, K., Ikeda, M., Rea, A., Guy, M., Lin, S., Cook, E. H., Jr., Chakravarti, A. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82: 160-164, 2008. [PubMed: 18179894, images, related citations] [Full Text]

  4. Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., Chawarska, K., Klin, A., Ercan-Sencicek, A. G., Stillman, A. A., Tanriover, G., Abrahams, B. S., Duvall, J. A., Robbins, E. M., Geschwind, D. H., Biederer, T., Gunel, M., Lifton, R. P., State, M. W. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82: 165-173, 2008. [PubMed: 18179895, images, related citations] [Full Text]

  5. Belloso, J. M., Bache, I., Guitart, M., Caballin, M. R., Halgren, C., Kirchhoff, M., Ropers, H.-H., Tommerup, N., Tumer, Z. Disruption of the CNTNAP2 gene in a t(7;15) translocation family without symptoms of Gilles de la Tourette syndrome. Europ. J. Hum. Genet. 15: 711-713, 2007. [PubMed: 17392702, related citations] [Full Text]

  6. Dawes, J. M., Weir, G. A., Middleton, S. J., Patel, R., Chisholm, K. I., Pettingill, P., Peck, L. M., Sheridan, J., Shakir, A., Jacobson, L., Gutierrez-Mecinas, M., Galino, J., and 28 others. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 97: 806-822, 2018. [PubMed: 29429934, images, related citations] [Full Text]

  7. Krumbiegel, M., Pasutto, F., Schlotzer-Schrehardt, U., Uebe, S., Zenkel, M., Mardin, C. Y., Weisschuh, N., Paoli, D., Gramer, E., Becker, C., Ekici, A. B., Weber, B. H. F., Nurnberg, P., Kruse, F. E., Reis, A. Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome. Europ. J. Hum. Genet. 19: 186-193, 2011. [PubMed: 20808326, images, related citations] [Full Text]

  8. Ma, D., Salyakina, D., Jaworski, J. M., Konidari, I., Whitehead, P. L., Andersen, A. N., Hoffman, J. D., Slifer, S. H., Hedges, D. J., Cukier, H. N., Griswold, A. J., McCauley, J. L., and 9 others. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73: 263-273, 2009. [PubMed: 19456320, images, related citations] [Full Text]

  9. Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G. Possible case of Pitt-Hopkins syndrome in sibs. Am. J. Med. Genet. 103: 157-159, 2001. [PubMed: 11568923, related citations] [Full Text]

  10. Penagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., Sonnenblick, L. I., Gruver, R., Almajano, J., Bragin, A., Golshani, P., Trachtenberg, J. T., Peles, E., Geschwind, D. H. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147: 235-246, 2011. [PubMed: 21962519, images, related citations] [Full Text]

  11. Poliak, S., Gollan, L., Martinez, R., Custer, A., Einheber, S., Salzer, J. L., Trimmer, J. S., Shrager, P., Peles, E. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron 24: 1037-1047, 1999. [PubMed: 10624965, related citations] [Full Text]

  12. Poot, M., Beyer, V., Schwaab, I., Damatova, N., van't Slot, R., Prothero, J., Holder, S. E., Haaf, T. Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Neurogenetics 11: 81-89, 2010. [PubMed: 19582487, related citations] [Full Text]

  13. Smogavec, M., Cleall, A., Hoyer, J., Lederer, D., Nassogne, M.-C., Palmer, E. E., Deprez, M., Benoit, V., Maystadt, I., Noakes, C., Leal, A., Shaw, M., Gecz, J., Raymond, L., Reis, A., Shears, D., Brockmann, K., Zweier, C. Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum. J. Med. Genet. 53: 820-827, 2016. [PubMed: 27439707, related citations] [Full Text]

  14. Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M., Stephan, D. A., Morton, D. H. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. New Eng. J. Med. 354: 1370-1377, 2006. [PubMed: 16571880, related citations] [Full Text]

  15. Verkerk, A. J. M. H., Mathews, C. A., Joosse, M., Eussen, B. H. J., Heutink, P., Oostra, B. A. The Tourette Syndrome Association International Consortium for Genetics : CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82: 1-9, 2003. [PubMed: 12809671, related citations] [Full Text]

  16. Vernes, S. C., Newbury, D. F., Abrahams, B. S., Winchester, L., Nicod, J., Groszer, M., Alarcon, M., Oliver, P. L., Davies, K. E., Geschwind, D. H., Monaco, A. P., Fisher, S. E. A functional genetic link between distinct developmental language disorders. New Eng. J. Med. 359: 2337-2345, 2008. [PubMed: 18987363, images, related citations] [Full Text]

  17. Zweier, C., de Jong, E. K., Zweier, M., Orrico, A., Ousager, L. B., Collins, A. L., Bijlsma, E. K., Oortveld, M. A. W., Ekici, A. B., Reis, A., Schenck, A., Rauch, A. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85: 655-666, 2009. [PubMed: 19896112, images, related citations] [Full Text]


Contributors:
Bao Lige - updated : 01/21/2020
Cassandra L. Kniffin - updated : 09/07/2017
Cassandra L. Kniffin - updated : 4/4/2012
Marla J. F. O'Neill - updated : 10/10/2011
Cassandra L. Kniffin - updated : 3/1/2010
Cassandra L. Kniffin - updated : 12/16/2009
Cassandra L. Kniffin - updated : 12/4/2009
Ada Hamosh - updated : 12/30/2008
Marla J. F. O'Neill - updated : 7/18/2008
Victor A. McKusick - updated : 6/6/2008
Cassandra L. Kniffin - updated : 1/29/2008
Victor A. McKusick - updated : 4/10/2006
Cassandra L. Kniffin - updated : 7/10/2003
Creation Date:
Patti M. Sherman : 2/18/2000
Edit History:
carol : 12/23/2021
carol : 12/23/2021
carol : 12/22/2021
mgross : 01/21/2020
alopez : 09/07/2017
ckniffin : 09/07/2017
carol : 09/30/2016
carol : 02/11/2015
mcolton : 2/10/2015
terry : 4/12/2012
terry : 4/6/2012
carol : 4/6/2012
ckniffin : 4/4/2012
carol : 10/13/2011
terry : 10/10/2011
wwang : 3/3/2010
ckniffin : 3/1/2010
wwang : 1/11/2010
ckniffin : 12/16/2009
wwang : 12/4/2009
alopez : 12/31/2008
terry : 12/30/2008
wwang : 7/21/2008
terry : 7/18/2008
alopez : 6/6/2008
alopez : 6/6/2008
wwang : 2/21/2008
ckniffin : 1/29/2008
alopez : 4/11/2006
alopez : 4/11/2006
terry : 4/10/2006
cwells : 11/10/2003
tkritzer : 8/13/2003
ckniffin : 7/10/2003
joanna : 5/16/2002
mgross : 2/25/2000
psherman : 2/21/2000

* 604569

CONTACTIN-ASSOCIATED PROTEIN-LIKE 2; CNTNAP2


Alternative titles; symbols

CONTACTIN-ASSOCIATED PROTEIN 2; CASPR2
NEUREXIN IV, DROSOPHILA, HOMOLOG OF; NRXN4


HGNC Approved Gene Symbol: CNTNAP2

Cytogenetic location: 7q35-q36.1   Genomic coordinates (GRCh38) : 7:146,116,801-148,420,998 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
7q35-q36.1 {Autism susceptibility 15} 612100 3
Pitt-Hopkins like syndrome 1 610042 Autosomal recessive 3

TEXT

Description

The CNTNAP2 gene encodes a neuronal transmembrane protein member of the neurexin superfamily involved in neural-glia interactions and clustering of potassium channels in myelinated axons. Rapid conduction in myelinated axons depends on the generation of specialized subcellular domains to which different sets of ion channels are localized. Contactin-associated protein (CNTNAP1; 602346) is another member of the neurexin superfamily (summary by Poliak et al., 1999).


Cloning and Expression

By searching sequence databases for homologs of CASPR, Poliak et al. (1999) identified several CASPR-related ESTs from various nervous system sources. They used 1 of these ESTs to isolate human brain and spinal cord cDNAs representing the entire CASPR2 coding sequence. The structural organization of the deduced 1,333-amino acid CASPR2 protein is very similar to that of CASPR and the related Drosophila Nrx IV, all having the hallmarks of type I transmembrane proteins. The extracellular region of CASPR2 is a mosaic of domains, including discoidin/neuropilin- and fibrinogen-like domains, 2 epidermal growth factor (EGF; 131530) repeats, and 4 domains similar to a region in laminin A (150320), referred to as the G domain. The extracellular region of CASPR2 also contains 12 potential N-linked glycosylation sites. CASPR2 has a short C-terminal region containing a binding site for type II PDZ domains. CASPR2 shares 45% amino acid sequence identity with CASPR and 34% identity with Drosophila Nrx IV. Recombinant CASPR2 expressed in mammalian cells had an apparent molecular mass of 180 kD. Northern blot analysis of human tissues detected 9- and 10-kb CASPR2 transcripts in brain, but only the 9-kb transcript in spinal cord. Low levels of CASPR2 mRNA were also detected in the ovary and prostate. The authors determined the expression pattern of CASPR2 within the adult human central nervous system. Like the spinal cord, the corpus callosum expressed only the 9-kb CASPR2 transcript. The 9-kb transcript was also the predominant transcript in the medulla, substantia nigra, and caudate nucleus. All the other regions examined, namely cerebellum, cortex, occipital pole, frontal lobe, temporal lobe, putamen, amygdala, hippocampus, subthalamic nucleus, and thalamus, expressed similar levels of the 9- and 10-kb CASPR2 transcripts. Immunolocalization of Caspr2 in adult rat brain demonstrated that Caspr2 is differentially expressed in distinct neuronal structures, including the soma and dendrites, and in specific short-segmented pairs along myelinated axons. Caspr2 expression in myelinated nerves was mostly confined to the axon at the juxtaparanodal region and to some isolated paranodal loops. In the juxtaparanodal region, Caspr2 precisely colocalized with Shaker-like potassium channels. Caspr2 specifically associated with Kv1.1 (176260), Kv1.2 (176262), and their Kv-beta-2 subunit (601142). This association involved the C-terminal region of Caspr2. Poliak et al. (1999) suggested that CASPR2 may stabilize the localization of potassium channels in the juxtaparanodal region, and that CASPR2 family members may play a role in the local differentiation of the axon into distinct functional subdomains.

Krumbiegel et al. (2011) performed comprehensive mRNA and protein expression analysis in ocular tissues from eyes with PEX syndrome/glaucoma (177650) and normal and glaucomatous control eyes. Quantitative real-time PCR showed ubiquitous expression of CNTNAP2 in virtually all ocular tissues with no significant difference between PEXS and control tissues. By immunohistochemistry, CNTNAP2 could be localized mainly to the cell membranes of epithelial and endothelial cells, the corneal endothelium, trabecular endothelial cells and endothelial cells lining the Schlemm canal, and iris pigment epithelium as well as the ciliary epithelium of both PEXS and control eyes. CNTNAP2 was also found to be expressed by vascular endothelial and smooth muscle cells, for example, in the conjunctival stroma, iris stroma, and choroidal stroma. In the retina, a marked labeling of retinal ganglion cells and retinal nerve fibers was present. Moreover, positive staining of the nerve fibers and glial cells was observed in the retrolaminar portion of the optic nerve. Electron microscopy with immunogold labeling confirmed a distinct reaction of cell membranes with CNTNAP2 antibodies, for example, in the basal membrane infoldings of nonpigmented ciliary epithelial cells. Krumbiegel et al. (2011) observed that in PEXS tissues, immunogold labeling of cell membranes appeared to be reduced close to cellular surface compartments from which the PEXS fibrils appeared to emerge.


Gene Structure

Alarcon et al. (2008) detected 24 exons in the CNTNAP2 gene.


Mapping

Poliak et al. (1999) noted that the CNTNAP2 gene had been mapped to chromosome 7q35-q36, between D7S688 and D7S505, using an STS.


Gene Function

Abrahams et al. (2007) used 2 sets of microarray analyses followed by selective in situ hybridization to identify differentially expressed genes in the superior temporal gyrus and cerebral cortex in midgestation human fetal brains. CNTNAP2 was consistently expressed at high levels in the prefrontal and anterior temporal cortex, as well as in the dorsal thalamus, caudate, putamen, and amygdala. In contrast to the findings in humans, Cntnap2 was broadly expressed in the developing rodent brain. Abrahams et al. (2007) noted that human CNTNAP2 expression was enriched in circuits involved in higher cortical functions, including language.

Vernes et al. (2008) found that the transcription factor FOXP2 (605317) directly regulates expression of CNTNAP2 by binding to a regulatory sequence in intron 1. Expression analysis of developing human cortex at 18 to 22 weeks' gestation showed complementary patterns of expression of FOXP2 and CNTNAP2 with respect to cortical lamination: CNTNAP2 expression was lowest in layers that showed highest levels of FOXP2. Vernes et al. (2008) identified CNTNAP2 polymorphisms with significant quantitative associations with nonsense-word repetition (see SLI4, 612514). The region containing these polymorphisms coincides with one associated with language delays in children with autism, as described by Arking et al. (2008). Mutations in the FOXP2 gene cause a monogenic speech and language disorder (602081). Vernes et al. (2008) concluded that by integrating functional genomics and quantitative trait analyses, they identified a shared neurogenetic pathway that is disturbed in specific forms of language impairment.


Cytogenetics

Verkerk et al. (2003) reported a family in which the father had obsessive-compulsive disorder (OCD; 164230) and both of his children, a girl and a boy, had Gilles de la Tourette syndrome (GTS; 137580), OCD, mental retardation, speech abnormalities, and growth retardation. All 3 individuals had a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The father had inv(2)(p23q22),ins(7;2) (q35-q36;p21p23) and the 2 affected children inherited the abnormal chromosome 7, sharing the 2p21-p23 insertion on 7q35-q36. Both children had a normal chromosome 2; thus both children had 3 copies of this region on chromosome 2. Fine mapping of the involved regions using FISH and BAC clones showed that the insertion interrupted the CNTNAP2 gene. Verkerk et al. (2003) hypothesized that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of potassium channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.

Belloso et al. (2007) reported a familial balanced reciprocal translocation t(7;15)(q35;q26.1) in phenotypically normal individuals, in which the 7q35 breakpoint disrupted the CNTNAP2 gene. The authors concluded that truncation of CNTNAP2 does not necessarily result in the Gilles de la Tourette syndrome.

Poot et al. (2010) reported a boy with autism, delayed motor development, mild ataxia with poor coordination, hyperactivity, poor speech development, outbursts, and some features of GTS. The authors described a highly complex chromosomal rearrangement involving at least 3 breaks in chromosome 1 and 7 breaks in chromosome 7 on the paternally derived chromosome. There was a de novo paracentric inversion of chromosome 7q32.1-7q35 that disrupted the CNTNAP2 gene. Additionally, 2 CNTNAP2 gene segments were inserted into a gene-poor region on the chromosome 1q31.2 region. There was also a de novo deletion encompassing the distal part of intron 1 and exon 2 of CNTNAP2, and a de novo deletion of chromosome 1q41, containing 15 annotated genes including KCTD3 (613272) and USH2A (608400), which has been reported as an autism susceptibility locus (AUTS11; 610836). Poot et al. (2010) suggested that haploinsufficiency for the CNTNAP2 gene may have caused the GTS features, and that the combination of CNTNAP2 disruption and 1q41 deletion may have acted together to result in full-blown autism.


Molecular Genetics

Pitt-Hopkins-Like Syndrome 1

Strauss et al. (2006) reported a homozygous mutation in the CNTNAP2 gene in Old Order Amish children with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), which the authors designated CDFE syndrome (cortical dysplasia-focal epilepsy syndrome). Temporal lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2. Four affected children and their 6 parents were used for analysis of SNPs in a microarray analysis. A large block of putative autozygosity was identified on chromosome 7q36. Sequencing of the CNTNAP2 gene revealed a 1-bp deletion (3709delG; 604569.0001), resulting in frameshift and a premature stop codon and predicted to yield a nonfunctional protein, owing to a lack of transmembrane and cytoplasmic domains. Genotype analysis of 105 healthy Old Order Amish controls revealed none who was homozygous for 3709delG but identified 4 carriers. Sequencing of the CNTNAP2 gene in 18 additional Old Order Amish patients with complex partial seizures identified the mutation in 9 additional patients from 7 sibships who had the characteristic clinical features of PTHSL1.

Zweier et al. (2009) identified homozygous or compound heterozygous mutations in the CNTNAP2 gene (604569.0005-604569.0007) in 2 sibs and 1 unrelated child with mental retardation, seizures, and hyperbreathing patterns, reminiscent of Pitt-Hopkins syndrome (see 610954). Dysmorphic features were not prominent. In Drosophila, overexpression of the CNTNAP2 homolog Nrxn4 resulted in increased density of synaptic active zones and reorganization of synaptic morphology, suggesting a role for this protein at the synapse.

In 8 patients from 6 unrelated families with PTHSL1, Smogavec et al. (2016) identified homozygous or compound heterozygous truncating mutations and/or intragenic deletions in the CNTNAP2 gene (see, e.g., 604569.0008-604569.0013). The patients were ascertained from different genetics or pediatric centers worldwide. The mutations and deletions were found by various methods, including microarray analysis, gene panel sequencing, and targeted sequencing. Carrier parents were unaffected, although 1 had anxiety and emotional lability; none underwent psychiatric testing. Functional studies of the variants were not performed, but all were predicted to result in a loss of function.

Susceptibility to Autism

Alarcon et al. (2008), Arking et al. (2008), and Bakkaloglu et al. (2008) identified SNPs in the CNTNAP2 gene (see, e.g., 604569.0002-604569.0004) that were associated with increased susceptibility to autism (AUTS15; 612100). In gene expression analyses in developing human brain, Alarcon et al. (2008) identified CNTNAP2 as enriched in circuits important for language development. By in situ and biochemical analyses, Bakkaloglu et al. (2008) confirmed expression of CNTNAP2 in relevant brain regions and demonstrated the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates.

Exfoliation Syndrome

For discussion of a possible association between variation in the CNTNAP2 gene and exfoliation syndrome, see 177650.

Animal Model

In Drosophila, Zweier et al. (2009) found that knockdown of Nrxn4 ubiquitously or specifically in neurons was embryonic lethal, with embryos failing to hatch. This was associated with decreased staining intensity of the presynaptic protein bruchpilot (nc82) in Nrxn4-knockdown embryos. Overexpression of Nrxn4 was associated with increased bruchpilot staining and changes in the morphologic organization of synapses. Examination of Drosophila larval neuromuscular junctions detected the presence of Nrxn4 at synaptic terminals localized in a pattern of subsynaptic foci that overlapped active zones. The findings of Nxrn4 were similar to that of Nxrn1 (600565), suggesting an overlapping function of these proteins.

Penagarikano et al. (2011) found expression of the Cntnap2 gene in various brain regions of embryonic mice beginning around embryonic day 14. Expression was observed in the ventricular proliferative zones of the developing cortex and ganglionic eminences, where excitatory projection neurons and inhibitory interneurons arise, respectively, and overlapped with regions containing migrating neurons and postmigratory cells, indicating a possible role in neuron development and/or migration. In the adult mouse, Cntnap2 was expressed in multiple brain regions, primarily cerebral cortex, hippocampus, striatum, olfactory tract, and cerebellar cortex. Cntnap2-null mice had no gross morphologic brain changes, but had ectopic neurons in the corpus callosum and deep cortex, reflecting a migration defect. Cntnap1 was found to be expressed in GABAergic inhibitory interneurons in normal mice, and these neurons were reduced in mutant mice. Neuronal firing in mutant mice was asynchronous compared to wildtype, and the mutant mice showed abnormal behavior, including increased locomotor activity, hyperreactivity to thermal sensory stimuli, stereotypic motor movements, and impaired communication and social interactions. These features were reminiscent of autism, and suggested that abnormal neuronal circuit architecture and firing underlie the disorder. Treatment of the mice with risperidone improved the motor behavioral abnormalities and improved nesting deficits, both likely mediated by the corticostriatal dopaminergic circuits, whereas other social behavior was not improved. The findings suggested distinct circuitries involved in these components of autism. Mutant mice also developed seizures at around 6 months of age.

Dawes et al. (2018) found that treatment with human CASPR2 antibodies caused pain-related hypersensitivity in mice. CASPR2 antibodies bound to peripheral nervous system, particularly at the level of dorsal root ganglion (DRG) neurons, but did not cause a gross neuroinflammatory response or damage the nervous system. Similarly, Caspr2 -/- mice displayed pain-related hypersensitivity with no major anatomic or transcriptional changes at the level of the DRG or spinal cord. Caspr2 cell-autonomously regulated excitability of DRG neurons by mediating membrane expression of Kv1 voltage-gated potassium channels. As a result, DRG neurons from Caspr2 -/- mice became hyperresponsive to mechanical and chemical stimuli. In addition, Caspr2 deletion resulted in hyperexcitability to D-hair primary afferents and dorsal horns. In support of these results, treatment of cultured mouse DRG neurons with human CASPR2 antibodies caused loss of membrane expression of Kv1 channels and increased their excitability.


ALLELIC VARIANTS 13 Selected Examples):

.0001   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1-BP DEL, 3709G
SNP: rs730880275, ClinVar: RCV000005825, RCV000255180

In Old Order Amish patients with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Strauss et al. (2006) identified a homozygous 1-bp deletion (3709delG) in exon 22 of the CNTNAP2 gene. The deletion was predicted to cause a frameshift that would result in the misincorporation of 16 amino acids beginning at position 1237. Premature termination of translation would occur at codon 1253. The mutation was predicted to yield a nonfunctional protein owing to the loss of the transmembrane and intracellular domains.


.0002   AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, IVS13, C-T
SNP: rs2710102, gnomAD: rs2710102, ClinVar: RCV000005826

In a 2-stage analysis of a 10-Mb quantitative trait locus for autism-related traits on 7q35-q36 (AUTS15; 612100) using parent-child trios, Alarcon et al. (2008) identified an association between variation at rs2710102 in the CNTNAP2 gene and age at first word in autism spectrum disorder samples from male-only families (p = 0.005). The authors noted that the SNP association results did not imply that variation at rs2710102 is causally related to autism spectrum disorder, but rather that variation here is likely to be in linkage disequilibrium with an untested functional variant.

A genomewide association study by Ma et al. (2009) of 438 Caucasian families with 1,390 individuals with autism and validation in an additional cohort of 2,390 samples from 457 families did not show a significant association between autism and rs2710102, which was the tagging SNP in the study of Alarcon et al. (2008). No tested markers linking to the CNTNAP2 gene were significant after correction.


.0003   AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, IVS2, A-T ({dbSNP rs7794745})
SNP: rs7794745, gnomAD: rs7794745, ClinVar: RCV000005827

In 2 independent family-based samples, Arking et al. (2008) identified a common variant in the CNTNAP2 gene, rs7794745, that was associated with increased risk for autism (AUTS15; 612100). This SNP resides in intron 2 of the CNTNAP2 gene. In the combined sample, overall transmission frequency of the T allele to affected children (tau = 0.55, p less than 7.35 x 10(05)) was significantly greater from mothers (tau = 0.61) than from fathers (tau = 0.53), and this parent-of-origin difference was significant (P less than 0.001).


.0004   AUTISM, SUSCEPTIBILITY TO, 15

CNTNAP2, ILE869THR
SNP: rs121908445, gnomAD: rs121908445, ClinVar: RCV000005828, RCV000711329, RCV001088251, RCV002426491

In 4 children with autism (AUTS15; 612100) from 3 unrelated families, Bakkaloglu et al. (2008) identified an ile869-to-thr (I869T) substitution in the CNTNAP2 protein. The mutation occurred at a conserved residue in the third laminin G domain and was predicted to be deleterious. In each family the variant was inherited from an apparently unaffected parent. The variant was not present in 4,010 control chromosomes.


.0005   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1.1-MB DEL, EX2-9
ClinVar: RCV000005829

In 2 sibs with Pitt-Hopkins-like syndrome-1 (PTHLS1; 610042) reported by Orrico et al. (2001), Zweier et al. (2009) identified a homozygous 1.1-Mb deletion of exons 2 through 9 of the CNTNAP2 gene. The patients had severe mental retardation, hyperbreathing, and seizures.


.0006   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, IVS10AS, G-T, -1
SNP: rs730880276, ClinVar: RCV000005830, RCV000187170

In a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Zweier et al. (2009) identified compound heterozygosity for 2 mutations in the CNTNAP2 gene: a G-to-T transversion in intron 10 and a 180-kb deletion of exons 5 through 8. The splice site was not identified in 384 controls chromosomes, and was predicted to result in the skipping of exon 10 and cause a frameshift and the loss of 2 laminin G domains. There was no CNTNAP2 expression in blood or fibroblasts. The patient had severe mental retardation with lack of speech, mildly delayed motor development, hyperbreathing, and seizures.


.0007   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 180-KB DEL, EX5-8
ClinVar: RCV000005831

For discussion of the 180-kb deletion of exons 5 through 8 in the CNTNAP2 gene that was found in compound heterozygous state in a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Zweier et al. (2009), see 604569.0006.


.0008   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, GLU494TER
SNP: rs149032771, gnomAD: rs149032771, ClinVar: RCV000505263

In a 12.5-year-old girl (patient 1) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified a homozygous c.1480G-T transversion (c.1480G-T, NM_014141) in exon 9 of the CNTNAP2 gene, resulting in a glu494-to-ter (E494X) substitution. The mutation, which was found by targeted sequencing of the CNTNAP2 gene, was heterozygous in both unaffected parents; it was found at a very low frequency (8 x 10(-6)) in the ExAC database in the heterozygous state. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.


.0009   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, EX1 DEL
ClinVar: RCV000505265

In a 2-year-old girl (patient 2) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified compound heterozygous mutations in the CNTNAP2 gene: the paternal allele carried a deletion of exon 1 (chr7.144,520,633-145,949,971, GRCh37), including loss of the start codon, whereas the maternal allele carried a c.3046C-T transition in exon 19, resulting in an arg1016-to-ter (R1016X; 604569.0010) substitution. The mutations were found by a combination of microarray analysis and direct sequencing; the R1016X mutation was not found in the ExAC database. Functional studies of the variants were not performed, but they were predicted to result in a complete loss of function.


.0010   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, ARG1016TER
SNP: rs371642222, ClinVar: RCV000505261, RCV001260690

For discussion of the c.3046C-T transition (c.3046C-T, NM_014141) in the CNTNAP2 gene, resulting in an arg1016-to-ter (R1016X) substitution, that was found in compound heterozygous state in a patient with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Smogavec et al. (2016), see 604569.0009.


.0011   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, EX9-10 DEL
ClinVar: RCV000505264

In 2 adult brothers (patients 4 and 5) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified compound heterozygous mutations in the CNTNAP2 gene: one allele carried a deletion of exons 9 and 10 (chr7.146,988,989-147,101,705, GRCh37), whereas the other carried a 1-bp deletion (c.2963delC; 604569.0012) in exon 18, resulting in a frameshift and premature termination (Cys989AlafsTer45). The parental origin of each mutation was discordant in the figure and table versus the text. The mutations were found by a combination of microarray analysis and genetic analysis of a multigene panel direct sequencing; the 1-bp deletion was not found in the ExAC database. Functional studies of the variants were not performed, but they were predicted to result in a complete loss of function.


.0012   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, 1-BP DEL, 2963C
SNP: rs1554400338, ClinVar: RCV000505266

For discussion of the 1-bp deletion ( c.2963delC, NM_014141) in the CNTNAP2 gene, resulting in a frameshift and premature termination (Cys989AlafsTer45), that was found in compound heterozygous state in 2 brothers with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042) by Smogavec et al. (2016), see 604569.0011.


.0013   PITT-HOPKINS-LIKE SYNDROME 1

CNTNAP2, CYS682TER
SNP: rs201076428, gnomAD: rs201076428, ClinVar: RCV000505262

In 2 brothers (patients 7 and 8) with Pitt-Hopkins-like syndrome-1 (PTHSL1; 610042), Smogavec et al. (2016) identified a homozygous c.2046C-A transversion (c.2046C-A, NM_014141) in exon 13 of the CNTNAP2 gene, resulting in a cys682-to-ter (C682X) substitution. The mutation, which was found by gene panel sequencing, segregated with the disorder in the family and was not found in the ExAC database. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function.


REFERENCES

  1. Abrahams, B. S., Tentler, D., Perederiy, J. V., Oldham, M. C., Coppola, G., Geschwind, D. H. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Nat. Acad. Sci. 104: 17849-17854, 2007. [PubMed: 17978184] [Full Text: https://doi.org/10.1073/pnas.0706128104]

  2. Alarcon, M., Abrahams, B. S., Stone, J. L., Duvall, J. A., Perederiy, J. V., Bomar, J. M., Sebat, J., Wigler, M., Martin, C. L., Ledbetter, D. H., Nelson, S. F., Cantor, R. M., Geschwind, D. H. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82: 150-159, 2008. [PubMed: 18179893] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.005]

  3. Arking, D. E., Cutler, D. J., Brune, C. W., Teslovich, T. M., West, K., Ikeda, M., Rea, A., Guy, M., Lin, S., Cook, E. H., Jr., Chakravarti, A. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82: 160-164, 2008. [PubMed: 18179894] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.015]

  4. Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., Chawarska, K., Klin, A., Ercan-Sencicek, A. G., Stillman, A. A., Tanriover, G., Abrahams, B. S., Duvall, J. A., Robbins, E. M., Geschwind, D. H., Biederer, T., Gunel, M., Lifton, R. P., State, M. W. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82: 165-173, 2008. [PubMed: 18179895] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.017]

  5. Belloso, J. M., Bache, I., Guitart, M., Caballin, M. R., Halgren, C., Kirchhoff, M., Ropers, H.-H., Tommerup, N., Tumer, Z. Disruption of the CNTNAP2 gene in a t(7;15) translocation family without symptoms of Gilles de la Tourette syndrome. Europ. J. Hum. Genet. 15: 711-713, 2007. [PubMed: 17392702] [Full Text: https://doi.org/10.1038/sj.ejhg.5201824]

  6. Dawes, J. M., Weir, G. A., Middleton, S. J., Patel, R., Chisholm, K. I., Pettingill, P., Peck, L. M., Sheridan, J., Shakir, A., Jacobson, L., Gutierrez-Mecinas, M., Galino, J., and 28 others. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 97: 806-822, 2018. [PubMed: 29429934] [Full Text: https://doi.org/10.1016/j.neuron.2018.01.033]

  7. Krumbiegel, M., Pasutto, F., Schlotzer-Schrehardt, U., Uebe, S., Zenkel, M., Mardin, C. Y., Weisschuh, N., Paoli, D., Gramer, E., Becker, C., Ekici, A. B., Weber, B. H. F., Nurnberg, P., Kruse, F. E., Reis, A. Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome. Europ. J. Hum. Genet. 19: 186-193, 2011. [PubMed: 20808326] [Full Text: https://doi.org/10.1038/ejhg.2010.144]

  8. Ma, D., Salyakina, D., Jaworski, J. M., Konidari, I., Whitehead, P. L., Andersen, A. N., Hoffman, J. D., Slifer, S. H., Hedges, D. J., Cukier, H. N., Griswold, A. J., McCauley, J. L., and 9 others. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73: 263-273, 2009. [PubMed: 19456320] [Full Text: https://doi.org/10.1111/j.1469-1809.2009.00523.x]

  9. Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G. Possible case of Pitt-Hopkins syndrome in sibs. Am. J. Med. Genet. 103: 157-159, 2001. [PubMed: 11568923] [Full Text: https://doi.org/10.1002/ajmg.1523]

  10. Penagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., Sonnenblick, L. I., Gruver, R., Almajano, J., Bragin, A., Golshani, P., Trachtenberg, J. T., Peles, E., Geschwind, D. H. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147: 235-246, 2011. [PubMed: 21962519] [Full Text: https://doi.org/10.1016/j.cell.2011.08.040]

  11. Poliak, S., Gollan, L., Martinez, R., Custer, A., Einheber, S., Salzer, J. L., Trimmer, J. S., Shrager, P., Peles, E. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron 24: 1037-1047, 1999. [PubMed: 10624965] [Full Text: https://doi.org/10.1016/s0896-6273(00)81049-1]

  12. Poot, M., Beyer, V., Schwaab, I., Damatova, N., van't Slot, R., Prothero, J., Holder, S. E., Haaf, T. Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Neurogenetics 11: 81-89, 2010. [PubMed: 19582487] [Full Text: https://doi.org/10.1007/s10048-009-0205-1]

  13. Smogavec, M., Cleall, A., Hoyer, J., Lederer, D., Nassogne, M.-C., Palmer, E. E., Deprez, M., Benoit, V., Maystadt, I., Noakes, C., Leal, A., Shaw, M., Gecz, J., Raymond, L., Reis, A., Shears, D., Brockmann, K., Zweier, C. Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum. J. Med. Genet. 53: 820-827, 2016. [PubMed: 27439707] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103880]

  14. Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M., Stephan, D. A., Morton, D. H. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. New Eng. J. Med. 354: 1370-1377, 2006. [PubMed: 16571880] [Full Text: https://doi.org/10.1056/NEJMoa052773]

  15. Verkerk, A. J. M. H., Mathews, C. A., Joosse, M., Eussen, B. H. J., Heutink, P., Oostra, B. A. The Tourette Syndrome Association International Consortium for Genetics : CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82: 1-9, 2003. [PubMed: 12809671] [Full Text: https://doi.org/10.1016/s0888-7543(03)00097-1]

  16. Vernes, S. C., Newbury, D. F., Abrahams, B. S., Winchester, L., Nicod, J., Groszer, M., Alarcon, M., Oliver, P. L., Davies, K. E., Geschwind, D. H., Monaco, A. P., Fisher, S. E. A functional genetic link between distinct developmental language disorders. New Eng. J. Med. 359: 2337-2345, 2008. [PubMed: 18987363] [Full Text: https://doi.org/10.1056/NEJMoa0802828]

  17. Zweier, C., de Jong, E. K., Zweier, M., Orrico, A., Ousager, L. B., Collins, A. L., Bijlsma, E. K., Oortveld, M. A. W., Ekici, A. B., Reis, A., Schenck, A., Rauch, A. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85: 655-666, 2009. [PubMed: 19896112] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.004]


Contributors:
Bao Lige - updated : 01/21/2020
Cassandra L. Kniffin - updated : 09/07/2017
Cassandra L. Kniffin - updated : 4/4/2012
Marla J. F. O'Neill - updated : 10/10/2011
Cassandra L. Kniffin - updated : 3/1/2010
Cassandra L. Kniffin - updated : 12/16/2009
Cassandra L. Kniffin - updated : 12/4/2009
Ada Hamosh - updated : 12/30/2008
Marla J. F. O'Neill - updated : 7/18/2008
Victor A. McKusick - updated : 6/6/2008
Cassandra L. Kniffin - updated : 1/29/2008
Victor A. McKusick - updated : 4/10/2006
Cassandra L. Kniffin - updated : 7/10/2003

Creation Date:
Patti M. Sherman : 2/18/2000

Edit History:
carol : 12/23/2021
carol : 12/23/2021
carol : 12/22/2021
mgross : 01/21/2020
alopez : 09/07/2017
ckniffin : 09/07/2017
carol : 09/30/2016
carol : 02/11/2015
mcolton : 2/10/2015
terry : 4/12/2012
terry : 4/6/2012
carol : 4/6/2012
ckniffin : 4/4/2012
carol : 10/13/2011
terry : 10/10/2011
wwang : 3/3/2010
ckniffin : 3/1/2010
wwang : 1/11/2010
ckniffin : 12/16/2009
wwang : 12/4/2009
alopez : 12/31/2008
terry : 12/30/2008
wwang : 7/21/2008
terry : 7/18/2008
alopez : 6/6/2008
alopez : 6/6/2008
wwang : 2/21/2008
ckniffin : 1/29/2008
alopez : 4/11/2006
alopez : 4/11/2006
terry : 4/10/2006
cwells : 11/10/2003
tkritzer : 8/13/2003
ckniffin : 7/10/2003
joanna : 5/16/2002
mgross : 2/25/2000
psherman : 2/21/2000



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
Printed: June 19, 2025