Common Questions

Written by Haley Oyler (SETBP1 parent) with approval by Dr Bregje van Bon (Clinical Geneticist at Radboud Medical Center in Nijmegen, Netherlands)

What is a SETBP1 Mutation?

A SETBP1 mutation, also known as a SETBP1 variant, is a genetic change within the SETBP1 gene located on chromosome 18. This gene contains the instructions to produce SETBP1 protein. The protein is shown to be active in numerous tissues, predominantly in the brain. This suggests that changes involving the SETBP1 gene may impact the development and/or function of brain cells. We also know that SETBP1 is a DNA-binding protein that forms part of a group of proteins that act together on histone methylation to make chromatin more accessible and regulate gene expression. The overall function of the SETBP1 protein is still largely unknown. A mutation within the SETBP1 gene means that some portion of this specific genetic code either got deleted, duplicated or rearranged. The Children’s Hospital in Philadelphia has a nice video describing mutations and variants.

What causes a SETBP1 Mutation?

A SETBP1 mutation occurs randomly and spontaneously in a germ cell (egg/sperm cell). The reasons for these DNA changes are unknown. Most cases are found to be de novo, which means that the change occurs spontaneously in the DNA of the egg or sperm that form the new child. In these cases, the parents do not have a SETBP1 mutation.

Who can get a SETBP1 Mutation?

Males and females of all races can be born with a DNA change in SETBP1. So far, approximately 250 individuals from many different countries all over the world, including Australia, Brazil, Bulgaria, Canada, China, England, France, Germany, Hungary, India, Italy, Japan, the Netherlands, Norway, Portugal, Spain, Sweden, the United States, and others have been identified. You can view a list of currently documented SETBP1-HD mutations HERE if you would like to see which mutations are known so far.

What does variant of unknown significance mean (VUS)?

There are typically 5 different classifications for an identified genetic variant. They are as follows:

Pathogenic – There is enough science and data to state that the variant is disease-causing. If this term is associated with the SETBP1 variant, then SETBP1 is causing challenges for your child.
Likely Pathogenic – There is science and data to state that the variant is most likely disease-causing. If this term is associated with the SETBP1 variant, then SETBP1 is likely causing challenges for your child.
Variant of Unknown Significance (VUS) – There is not enough data and science to know if the variant is causing the challenges your child is facing. There are several ways that a VUS can be reclassified as a pathogenic or a benign variant. If more individuals are identified with the same variant with a similar phenotype, then the VUS will likely change to a pathogenic variant. A good example is the SETBP1 missense variant c.2572G>A (p.Glu858Lys). This variant has been classified as a VUS; however, several individuals with this SETBP1 mutation have a similar phenotype. This variant should state pathogenic on genetic reports moving forward. On the other hand, if numerous individuals within the healthy population (meaning that the individuals do not have signs of SETBP1-HD) are identified to have the SETBP1 variant, then the specific variant is likely to be classified in the future as benign. You can see these classifications described a bit more in this Exome Sequencing video by Children’s Hospital of Philadelphia (CHOP).
Likely Benign – The known data and science indicate that the variant is not likely the cause for the challenges your child is facing. There is likely another cause for their challenges.
Benign – The known data and science indicate that the variant is not the cause for the challenges your child is facing. There is a different cause for their challenges.

What is SETBP1 haploinsufficiency disorder (SETBP1-HD, SETBP1 disorder)?

SETBP1 haploinsufficiency disorder (SETBP1-HD) is a neurodevelopmental disorder caused by a loss-of-function change in one of the two copies of the SETBP1 gene or the deletion of one copy of the SETBP1 gene. The one copy of the SETBP1 gene does not produce a sufficient amount of SETBP1 protein for the body to function normally. This is also known as haploinsufficiency, which is where SETBP1 haploinsufficiency disorder derives its name. On genetic reports, the description may state something like “This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay”. SETBP1 mutations within the hotspot region 868-871 that result in an overproduction or accumulation of the SETBP1 protein result in a progressive, genetic syndrome called Schinzel-Giedion Syndrome. SETBP1 mutations, within the 862-867 or 872-873 region, which are located just outside the hotspot region and result in an overproduction or accumulation of the SETBP1 protein result in a less-severe form of Schinzel-Giedion Syndrome called atypical Schinzel-Giedion Syndrome. SETBP1 haploinsufficiency disorder and Schinzel-Giedion Syndrome are 2 distinct genetic conditions. SETBP1 haploinsufficiency disorder may also be listed as Mental Retardation Autosomal Dominant 29 (MRD29) or SETBP1-related disorder on some genetic reports and on some medical websites. Check out this short video titled “What is SETBP1-HD”?

Is SETBP1 disorder and SETBP1 haploinsufficiency disorder the same?

Yes, SETBP1 disorder and SETBP1 haploinsufficiency disorder refer to the same neurodevelopmental disorder. Haploinsufficiency is quite the mouthful but helps to explain medically what is causing the disorder. Haploinsufficiency occurs when one copy of a gene is inactivated or deleted and the remaining functional copy of the gene is not sufficient to produce the needed gene protein to preserve normal function. Kids with SETBP1-HD have one functioning copy of the SETBP1 gene which is insufficient for normal function. You will begin to see SETBP1 haploinsufficiency disorder in medical literature while SETBP1 Society and the SETBP1 community will refer to it as SETBP1-HD. SETBP1 disorder was the original name referred to the disorder before a more molecularly meaningful name was established.

What is SETBP1-related disorders?

The term SETBP1-related disorders refers to a heterogeneous disorder associated with symptoms that overlap with SETBP1 haploinsufficiency disorder and Schinzel-Giedion Syndrome from SETBP1 variants that are not missense variants in the Schinzel-Giedion Syndrome region and do not cause haploinsufficiency.

What are the symptoms of SETBP1 haploinsufficiency disorder (SETBP1-HD)?

Symptoms can vary from individual to individual depending on the type, location, and size of the mutation, but the most common traits are speech delays ranging from apraxia of speech to non verbal, global developmental delay, intellectual disability, autistic traits/autism, adhd, very social, fine and gross motor delays, and hypotonia (low tone). Some other noted symptoms are seizures, feeding issues, sleep disturbances, gastrointestinal issues, anxiety, reading and writing disorders, and minor facial differences. For a detailed list of additional symptoms, please check out the symptoms list at What is SETBP1. You can also check out the latest SETBP1-HD Resource Guide.

Is there a cure?

At this time, there is no cure for SETBP1-HD.

What are the treatments?

While there is no cure for a SETBP1 change, speech, occupational, and physical therapies can help manage symptoms in children and also help them reach developmental milestones. Seizures, if present, are treated by a specialist. Some parents in the SETBP1 parent group have reported an improvement in attention and focus for children with SETBP1-HD taking stimulants/ADHD medications. For more information, parents of children with SETBP1-HD can join our SETBP1 Facebook Support Group. Other resources can be viewed at our Resources page.

Where can I point medical professionals to learn more about SETBP1-HD?

The best available resource for medical professionals is the SETBP1 Haploinsufficiency Disorder Gene Review.

How is a SETBP1 mutation diagnosed?

SETBP1 changes are not diagnosed easily. Often children with SETBP1-HD will have normal MRIs, normal EEGs, and normal chromosome pairings – common tests that can often help diagnose other, more common genetic disorders. In most instances, SETBP1-HD mutations are discovered through a genetic blood test called Whole Exome Sequencing (WES) – Learn more. This blood test examines the individual’s entire genetic makeup. This is compared with the genetic sequences of the parents. Through this test, rare genetic outliers like SETBP1 changes can be determined and diagnosed. It is important to note that this test has only really become more widely available and covered by insurance in the past several years, which explains why there are so few known individuals. As this test becomes more prevalent, we expect the number of individuals diagnosed with a SETBP1 change to grow. Another test that is now available is the Whole Genome Sequencing test. This test will also identify individuals with SETBP1-HD.

How do I read my child’s genetic report?

Simons Searchlight, the organization that hosts our official SETBP1 registry, provided an informative video during our 2020 family conference that walks individuals step by step through reading a sample genetic report. Check out the How to Read your Genetic Report (gene change) video. If your child has a deletion including part or all of the SETBP1 gene instead of a change within the SETBP1 gene, then you may want to check out the How to Read your Genetic Report (CNV) video. If you want to learn more about genetics, the Genetics 101 session is good to check out.

What is the prognosis?

To date, we do not know of any deaths that have occurred in individuals with SETBP1-HD due to complications with SETBP1 changes. Also, this disorder does not appear to be progressive, meaning it does not worsen over time. As more and more individuals are diagnosed with SETBP1-HD, the phenotype and prognosis will continue to evolve.

What can I do to help?

For parents with children with SETBP1-HD, consider joining our official SETBP1 Society registry. SETBP1 Society has partnered with Simons VIP to collect natural history information for individuals identified with SETBP1 variants. You can find out more ways to participate in research HERE.

Consider making a donation to our organization. You can consider setting up a Facebook Birthday Fundraiser, or consider hosting a fundraiser. Your donations will help us further our mission. Please like and follow our SETBP1 Society Facebook page for updates on additional ways to help.

Think about participating in SETBP1-HD research. You can view research opportunities HERE.

SETBP1 Society is a volunteer-based organization and every Board member generously dedicates their time and energy. If you have any experience in the following areas – fundraising, graphic design, social media management, accounting and/or legal or have a responsible high school/college student looking for volunteer hours – please reach out to our organization at info@setbp1.org.

How do I join the SETBP1 community?

If you are the parent of a child with a SETBP1 difference, consider joining our SETBP1 Facebook group. Also, you can sign up for the SETBP1 Society newsletter to keep up-to-date on SETBP1-related communications by completing the short form on the Newsletters page. If you are a grandparent, aunt or other extended family member of a child with SETBP1-HD, a supportive friend, a researcher, or a medical specialist interested in SETBP1-HD, consider joining our SETBP1 Friends and Family Facebook group.

You can check out our SETBP1 community map at http://www.setbp1.org/community-map to see where other SETBP1 families live!

What other resources are available?

Read the SETBP1-HD Guide.
Read the SETBP1-HD Information Sheet.
Read the latest publications about SETBP1 haploinsufficiency disorder (SETBP1-HD): Clinical delineation of SETBP1 haploinsufficiency disorder and Speech and language deficits are central to SETBP1 haploinsufficiency disorder.
My child received the diagnosis, what’s next? When your child is diagnosed with Special Needs and Support and Self Care.
Check out our Resources page for more information

Where can I learn more about genetics?

We developed a Genetics 101 page to further describe genetic differences in our body.
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