CNTNAP2
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.
Mutations
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
Incidence
Exact numbers of patients with CNTNAP2 mutations are not known, but publically-accessible databases have already catalogued several hundred pathogenic variants present in patients:
- 135 pathogenic and likely pathogenic mutations are catalogued in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar).
- 23 pathogenic and likely pathogenic mutations are recorded in Geisinger Database (https://dbd.geisingeradmi.org/site/CNTNAP2),
- 188 sequence and copy number variants out of 39,000 cases of Rare genetic disorders (1 in 211) have been recorded in Decipher (https://www.deciphergenomics.org/gene/CNTNAP2/patient-overlap/cnvs).
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.
https://omim.org/entry/610042#description
https://rarediseases.info.nih.gov/diseases/11967/pitt-hopkins-like-syndrome
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).
https://omim.org/entry/610042#description
Mutations in CNTNAP2 are also associated with susceptibility to autism (AUTS15).
Symptoms
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:
- Varea O, Martin-de-Saavedra MD, Kopeikina KJ, Schürmann B, Fleming HJ, Fawcett-Patel JM, Bach A, Jang S, Peles E, Kim E, Penzes P. Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6176-81. doi: 10.1073/pnas.1423205112. Epub 2015 Apr 27. PMID: 25918374; PMCID: PMC4434727.
- Gao R, Piguel NH, Melendez-Zaidi AE, Martin-de-Saavedra MD, Yoon S, Forrest MP, Myczek K, Zhang G, Russell TA, Csernansky JG, Surmeier DJ, Penzes P. CNTNAP2 stabilizes interneuron dendritic arbors through CASK. Mol Psychiatry. 2018 Sep;23(9):1832-1850. doi: 10.1038/s41380-018-0027-3. Epub 2018 Apr 9. PMID: 29610457; PMCID: PMC6168441.
- Gao R, Zaccard CR, Shapiro LP, Dionisio LE, Martin-de-Saavedra MD, Piguel NH, Pratt CP, Horan KE, Penzes P. The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons. Neurosci Lett. 2019 May 14;701:92-99. doi: 10.1016/j.neulet.2019.02.025. Epub 2019 Feb 16. PMID: 30779956; PMCID: PMC6508520.
- Gao R, Pratt CP, Yoon S, Martin-de-Saavedra MD, Forrest MP, Penzes P. CNTNAP2 is targeted to endosomes by the polarity protein PAR3. Eur J Neurosci. 2020 Feb;51(4):1074-1086. doi: 10.1111/ejn.14620. Epub 2019 Dec 2. PMID: 31730244; PMCID: PMC7069803.
Important publications form other laboratories
- Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006 Mar 30;354(13):1370-7. doi: 10.1056/NEJMoa052773. PMID: 16571880.
- Rodenas-Cuadrado, P., Ho, J. & Vernes, S. Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet 22, 171–178 (2014).
- Peñagarikano O, Geschwind DH. What does CNTNAP2 reveal about autism spectrum disorder? Trends Mol Med. 2012 Mar;18(3):156-63.
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
E-mail: phrf@pitthopkins.org
Website: http://pitthopkins.org/
Social Media ResourcesConnect with communities focused on this topic.
Connect with communities focused on this topic.