Last updated:
4/23/2025
Years published: 2025
NORD gratefully acknowledges As Healthy As Possible, Marissa Vawter-Lee, MD, Child Neurology, Cincinnati Children’s Hospital Medical Center, Associate Professor, University of Cincinnati Department of Pediatrics and Cincinnati Children’s Department of Child Neurology; Michael F. Wells, PhD, Principal Investigator, UCLA David Geffen School of Medicine; and Christine Erdie-Lalena, MD, FAAP, Developmental Behavioral Pediatrician, Atrium Health Levine Children’s, for the preparation of this report.
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Summary
POLR2A-related disorder is a genetic condition caused by changes (variants) in the POLR2A gene. It is characterized that can include developmental delay, low muscle tone (hypotonia), autistic behaviors, seizures (of varying type and intensity) and abnormalities in the muscle and skeletal systems of the body. Psychiatric symptoms have also been reported.1,2,3,4 Onset is typically during the infant and toddler years. The condition is generally noticed as a child begins to miss developmental milestones. Diagnosis is confirmed through genetic testing. The first publication about a POLR2A-related disorder was in 2019 and there are less than 100 reports in the medical literature.1 There is currently no known treatment for POLR2A-related disorder, but symptoms such as seizures can be treated with anti-epileptic medications. While challenges may exist, some affected children have been reported as enjoying a good quality of life.
POLR2A-related disorder is a rare genetic condition that can affect multiple systems in the body. Symptoms can vary from person to person but usually the affected person has neurological and developmental delays.
Common symptoms may include:
Other possible symptoms may include:
MRI exams may show brain abnormalities such as delayed development of white matter in the brain, shrinkage (atrophy) of the white matter, thin or absent corpus callosum (the structure that connects both brain hemispheres), enlarged brain ventricles (ventriculomegaly), shrinkage of the part of the brain (cerebellum) that controls movement (cerebellar atrophy), shrinkage of the lower part (brainstem) of the brain, periventricular cysts (fluid-filled spaces in the brain) and abnormal brain folds (polymicrogyria).
Some gene variants in related polymerase genes have been linked to an increased risk of cancer. However, there is no known connection between POLR2A-related disorder and cancer at this time, though one case of ependymoma (a rare brain tumor) has been reported.5
The POLR2A gene, also known as RNA polymerase II subunit A gene, is a gene that has an important function in how cells make proteins. It has instructions to make (codify) the largest subunit of RNA polymerase II, an enzyme responsible for the transcription process of DNA into messenger RNA (mRNA). Transcription is the process of making an RNA copy of a gene’s DNA sequence. This process is essential because mRNA carries genetic instructions to produce proteins that support cell growth, function and repair.
RNA polymerase II is a complex enzyme made up of 12 subunits, with POLR2A being the largest and most important. The POLR2A gene provides instructions for making a protein that is part of the DNA-binding domain of RNA polymerase II. This domain forms a groove where DNA is read and transcribed into RNA. 6 Therefore, this enzyme plays an important regulatory role in the body.
POLR2A is expressed in many different tissues, including the nervous system (brain, spinal cord), digestive system, urinary and reproductive systems and the skin and sensory organs. Therefore, abnormalities in POLR2A can affect multiple body systems, leading to a wide range of symptoms.
Inheritance
Typically, variants in the POLR2A gene are “de novo,” meaning that they are not inherited from a parent. There are reports about truncating and missense variants and in-frame deletions 1,2 A “truncating” variant refers to a variant that prematurely stops protein synthesis resulting in a shortened protein; “missense” describes a variant where a single nucleotide change leads to a different amino acid being coded for in the protein and “in-frame deletion” is a loss (deletion) of DNA nucleotides that does not disrupt the reading frame, meaning the protein is still produced but may be shorter than normal. There has been a published study of a POLR2A variant inherited as an autosomal dominant condition.2
As of 2025, about 99 people have been diagnosed worldwide with POLR2A-related disorder. No specific population has been reported to have a greater occurrence of the condition. No diagnoses of this condition have been confirmed in Africa.
The diagnosis may be suspected in an infant or toddler with hypotonia, global developmental delay and abnormal MRI imaging. A diagnosis of POLR2A-related disorder can be confirmed with genetic testing.
There is currently no genetic therapy available for direct treatment. Interventions and management of the disorder are symptom specific. These may include specialized feeding techniques/therapies, physical therapy, occupational therapy and speech/language therapy including adaptive communication techniques. Additional durable medical equipment supports could be necessary and may include pediatric standers, walkers, orthotic supports, safety beds and activity chairs.
Medical specialists who may be included for check-ups after diagnosis or in a multidisciplinary care team can include genetics, child neurology, pediatric cardiology, pediatric pulmonology, pediatric gastroenterology, pediatric physiatry (rehabilitation) and developmental and behavioral pediatrics.
A natural history study is being led by the University of Pittsburgh which has also established a patient registry for individuals who have been diagnosed with this rare disorder or have been identified as having a variant in the POLR2A gene or other POLR2 gene. The purpose of a patient registry is to compile information on gene variants and associated symptoms and to potentially follow patients over time. This research aims to understand the full diversity of symptoms and how these symptoms may relate to specific POLR2 gene variants. Participation in the study involves filling out surveys on patient health, demographic information and genetic testing information. The single criterion for eligibility is that study participants must have had genetic testing that indicates a POLR2A gene variant or variant in another POLR2 gene. Contact [email protected] or the POLR2A patient advocacy group at [email protected] for more information.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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 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:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
INTERNET
POLR2A Parents Facebook Group: https://www.facebook.com/groups/779639105806149 Accessed April 14, 2025.
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