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Mutations in the CNTNAP2 gene cause a syndromic neurodevelopmental disorder characterized by intellectual disability, speech impairment, early-onset seizures, developmental regression, and autism. This condition is referred to as cortical dysplasia - focal epilepsy (CDFE), Pitt-Hopkins-like Syndrome 1 (PHLS1), or CNTNAP2-related developmental and epileptic encephalopathy. CNTNAP2 mutations have also been found in schizophrenia patients. While this condition is rare, with currently 28 affected individuals known, it is expected that genetic testing will reveal thousands more. Below we summarize current knowledge and useful information about this gene.

 Biological Function

  • The CNTNAP2 gene encodes Contactin-associated protein 2 or CASPR2, a neuronal cell-adhesion protein.
  • CNTNAP2 is the largest gene in the human genome.
  • In the brain and the rest of the nervous system, the CNTNAP2 protein is involved in interactions between neurons and between neurons and glial cells.
  • The CNTNAP2 protein plays key roles in connecting brain cells with each other at synapses, and in clustering of potassium channels. 
  • This protein plays key roles in brain development, in particular of the cerebral cortex.
  • It is one of the few known genes essential for development of language.
  • Deletion of the gene in mouse models recapitulates symptoms in humans, namely seizures, learning deficits, and abnormal communication.


The CNTNAP2 gene has been implicated in multiple neurodevelopmental disorders, including autism, intellectual disability, schizophrenia, epilepsy, and ADHD. In most cases, absence or mutation in only one copy of the gene is sufficient to case disease. However, mutations in this gene do not always cause disease; carriers may be at higher risk of developing a disease or be normal. The image below shows the map of the gene, the proteins domains encoded, the position of known mutations as well as the associated diagnoses.

Image from: Rodenas-Cuadrato et al., 2014


Exact numbers of patients with CNTNAP2 mutations are not known, but publically-accessible databases have already catalogued several hundred pathogenic variants present in patients:

This suggests that while currently considered rare, CNTNAP2-related disorders may in fact affect thousands of people worldwide.

 Associated Conditions

While patients with mutations in the CNTNAP2 gene have been individually diagnosed with several neurodevelopmental disorders, CNTNAP2 mutations are most closely associated with Pitt-Hopkins-Like Syndrome 1 (PTHSL1) or Cortical Dysplasia-Focal Epilepsy Syndrome (CDFES). These syndromes have been initially reported separately, but now are considered the same. 

According to Online Mendelian Inheritance (OMIM) and NIH’s Rare Diseases Database (XXX), PTHSL1 (610042) is an autosomal recessive genetic neurodevelopmental disorder characterized by intellectual disability, delayed psychomotor development, severe speech impairment or regression, abnormal sleep, breathing abnormalities, early-onset seizures, unusual facial features, and behavioral abnormalities such as autistic behavior and stereotypic movements. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging.

In other studies, a mutation in CNTNAP2 gene was found in several members of a kindred of Old Order Amish patients diagnosed with cortical dysplasia-focal epilepsy syndrome (Strauss et al., 2006).

Mutations in CNTNAP2 are also associated with susceptibility to autism (AUTS15).


Between 80-90% of patients with CNTNAP2 mutations have the following symptoms: absent speech, impaired social interactions, muscular hypotonia, severe intellectual disability, severe global developmental delay and repetitive movements. Between 30-79% of patients show unusual facial shape, constipation, and failure to thrive. A fraction of patients are show aggressive behavior, self injury, and other symptoms. (XXX)

 Research at Northwestern

Research projects at CAN are investigating how mutations in CNTNAP2 lead to neurodevelopmental disorder, aiming to use this knowledge to develop new treatments. 

For more information, visit the Penzes lab

Below are links to some of the publications from CAN on CNTNAP2:

 Important publications form other laboratories

 Genetic Testing

Genetic tests can detect mutations in CNTNAP2. As of now, they are not performed at NU; find information about existing tests.

 Clinical Trials

While there are currently no clinical trials specifically for CNTNAP2-associated mutations, there are a few clinical trials for Pitt-Hopkins syndrome.

 Patient advocacy organizations

Currently, there is no patient advocacy organization or foundation focusing specifically on patients with mutations in the CNTNAP2 gene. Such an organization could direct public attention and funds toward research and treatment development for patients with CNTNAP2 mutations, could promote scientific exchange, provide support to families of patients, and facilitate clinical trials.

Currently, the Pitt-Hopkins Research Foundation includes Pitt Hopkins-like syndrome-1 under its umbrella. Patients with PTHLS1 may not present the same facial features as individuals with Pitt-Hopkins Syndrome, but share many of the same issues such as global developmental delay, seizures, lack of speech, breathing irregularities, and autistic features.

Pitt Hopkins Research Foundation

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