Last updated:
7/11/2023
Years published: 2023
NORD gratefully acknowledges Madeline Cesarone, Genetic Counseling Student, Baylor College of Medicine, Kate Richardson, MS, CGC and Hope Northrup, MD, McGovern Medical School, UTHealth Houston, for the preparation of this report.
Summary
TANC2-related disorders are categorized as a neurodevelopmental syndrome with associated psychiatric findings. This condition is caused by changes (disease-causing variants) in the TANC2 gene. Characteristics of this disorder include autism, developmental delay, seizures, sleep disturbances, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability. It is important to note that these features can also have different genetic causes.
TANC2-related disorders are reported to have variable expressivity, meaning there is a range of symptoms that can occur in people affected with this genetic condition. In addition to the symptoms mentioned above, common symptoms include delayed motor development, delayed speech development and some patients have been reported with seizures (epilepsy). Additional features seen in patients affected with TANC2-related disorders are chronic constipation, distinct facial features that vary within a family and walking difficulties. The average age of onset for many symptoms begins in childhood.
Introduction
TANC2-related disorders were first defined in 2019, therefore, this disorder has a wide and evolving spectrum of neurodevelopmental and psychiatric symptoms.
The TANC2 gene holds instructions for creating (encoding) a protein called TANC2. This protein helps control connections between brain cells (synapse scaffold proteins). Having proper support for the synapse allows nerve cells to respond to stimuli. Genetic changes in the TANC2 gene lead to abnormally shaped proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.
Individuals with TANC2-related disorders have a spectrum of neurodevelopmental conditions. These can include autism, intellectual disability, language delays and motor delays. There have been reports of patients with a TANC2 genetic change having seizures. In these patients, brain imaging is typically normal. Some adult patients display psychiatric conditions such as schizophrenia, bipolar disorder and compulsive behavior. Dysregulation of non-voluntary body functions (dysautonomia) has also been documented. Low blood pressure, feeling faint, excessive or lack of sweating, fatigue, trouble swallowing, fast or slow heart rate, anxiety and drooling are all symptoms of dysautonomia.
Other reported features of TANC2-related disorders include chronic constipation; walking difficulties; differences in facial features (widely spaced front teeth, large ears, thick eyebrows, large mouth); smaller head size (microcephaly) and sleep disturbances.
TANC2-related disorders are caused by changes (pathogenic variants) in the TANC2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect different parts of the body. Typically, the genetic change in TANC2 is new in the patient (de novo). This means that it was not inherited from either parent. However, there have been rare instances of a patient inheriting a pathogenic variant in the TANC2 gene from a parent.
The TANC2 gene holds instructions for creating (encoding) a protein called tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (TANC2). This protein interacts with postsynaptic density (PSD) proteins. PSD proteins are attached to the surface of the postsynaptic membrane that receives chemical signals and sends signals to target cells. Target cells can include nerve cells or muscle cells. Healthy PSD proteins facilitate sending signals constantly between cells. In short, the TANC2 protein helps the brain communicate within the brain and with other body parts. Genetic changes in the TANC2 gene lead to abnormally shaped TANC2 proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.
TANC2-related disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the TANC2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Males and females have the same level of risk, and the risk of passing a non-working gene to offspring is 50% for each pregnancy.
In 2019, Hui Guo, et al reported the first 20 patients with known disease-causing (pathogenic) TANC2 variants. TANC2-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders like TANC2-related disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population.
A diagnosis of TANC2-related disorder is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the TANC2 gene. A clinical diagnosis cannot be used for this disorder.
There is currently no cure for TANC2-related disorders. Treatment is based on the medical problems that are present in an affected person. Due to the rarity of this condition, treatments have not been studied in a large group of patients. There are no standardized treatment protocols or guidelines for affected individuals.
A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), speech pathologists, physical therapists and other healthcare professionals can be involved in care. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Management can include speech and language therapy; occupational therapy; physical therapy; neurodevelopmental assessments for academic ability; gastrointestinal evaluation to assess for constipation and prescription of antiepileptic medications.
Information on current clinical trials is posted on the internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Guo H, Bettella E, Marcogliese PC, et al. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nature Communications. 2019;10(1). doi:10.1038/s41467-019-12435-8
Coe BP, Stessman HA, Sulovari A, et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nature Genetics. 2018;51(1):106-116. doi:10.1038/s41588-018-0288-4
Grozeva D, Carss K, Spasic‐Boskovic O, et al. Targeted next‐generation sequencing analysis of 1,000 individuals with intellectual disability. Human Mutation. 2015;36(12):1197-1204. doi:10.1002/humu.22901
Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179-184. doi:10.1038/nature12929
Han S, Nam J, Li Y, et al. Regulation of dendritic spines, spatial memory, and embryonic development by the Tanc family of PSD-95-interacting proteins. The Journal of Neuroscience. 2010;30(45):15102-15112. doi:10.1523/jneurosci.3128-10.2010
Shilyansky C, Lee YS, Silva AJ. Molecular and cellular mechanisms of learning disabilities: A focus on NF1. Annual Review of Neuroscience. 2010;33(1):221-243. doi:10.1146/annurev-neuro-060909-153215
INTERNET
Online Mendelian Inheritance in Man (OMIM). Entry #618906. Intellectual Developmental Disorder with Autistic Features and Language Delay, With or Without Seizures; IDDALDS. Updated 06/18/2020. https://www.omim.org/entry/618906 Accessed July 11, 2023.
Geisinger Developmental Brain Disorder Gene Database. TANC2. Geisinger DBD Genes Database (geisingeradmi.org). Accessed July 11, 2023.
TANC2 Facebook group. (1) TANC2 | Facebook
TANC2: Simons Searchlight Community Facebook group. (1) TANC2: Simons Searchlight Community | Facebook
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