SETD2-Related Syndrome
SETD2-related syndrome is also called autosomal dominant intellectual developmental disorder-70 (MRD70), Luscan-Lumish syndrome, and Rabin-Pappas syndrome (RAPAS) or SETD2 neurodevelopmental disorder with multiple congenital anomalies. For this webpage, we will be using the name SETD2-related syndrome to encompass the wide range of variants observed in the people identified.
What is SETD2-related syndrome?
SETD2-related syndrome happens when there are changes in the SETD2 gene. These changes can keep the gene from working as it should.
Key Role
The SETD2 gene controls the activity of other genes and is important for brain function.
Symptoms
Because the SETD2 gene is important for brain activity, many people who have SETD2-related syndrome have:
- Intellectual disability
- Speech delay
- Larger than average head size in some people
- Smaller than average head size in some people
- Overgrowth and/or obesity
- Failure to thrive
- Advanced bone age
- Autism
- Low muscle tone
- Seizures
- Vision issues
- Hearing loss
- Heart defects
- Urinary tract defects
- Brain changes seen on magnetic resonance imaging (MRI)
What causes SETD2-related syndrome?
SETD2-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the SETD2 gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.
Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.
De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because SETD2 plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that SETD2-related syndrome is often the result of a de novo variant in SETD2. Many parents who have had their genes tested do not have the SETD2 genetic variant found in their child who has the syndrome. In some cases, SETD2-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
SETD2-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in SETD2 they will likely have symptoms of SETD2-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.
Autosomal Dominant Genetic Syndrome
Why does my child have a change in the SETD2 gene?
No parent causes their child’s SETD2-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.
What are the chances that other family members or future children will have SETD2-related syndrome?
Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.
The risk of having another child who has SETD2-related syndrome depends on the genes of both biological parents.
- If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant.
- If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent.
For a symptom-free brother or sister of someone who has SETD2-related syndrome, the sibling’s risk of having a child who has SETD2-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing SETD2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit SETD2-related syndrome.
- If one biological parent has the same genetic variant causing SETD2-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent.
For a person who has SETD2-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have SETD2-related syndrome?
As of 2026, about 54 people in the world with changes in the SETD2 gene had been described in medical research. The first case of SETD2-related syndrome was described in 2012. Scientists expect to find more people who have the syndrome as access to genetic testing improves.
Do people who have SETD2-related syndrome look different?
People with SETD2-related syndrome may look different. Appearance can vary and can include, but is not limited to, these features:
- Smaller than average head size (microcephaly)
- Larger than average head size (macrocephaly)
- Low muscle tone
- Noticeable forehead
- Undersized lower jaw
How is SETD2-related syndrome treated?
Scientists and doctors have only just begun to study SETD2-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:
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- Physical exams and brain studies
- Genetics consults
- Development and behavior studies
- Other issues, as needed
A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:
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- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for SETD2-related syndrome should begin as early as possible, ideally before a child begins school.
If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.
This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.
Behavior and development concerns linked to SETD2-related syndrome
Problematic variants in SETD2 can result in three different conditions: Luscan-Lumish syndrome, Rabin-Pappas syndrome, and autosomal dominant intellectual developmental disorder-70 (MRD70). The condition a person has will depend on the location of the variant in the SETD2 gene. The information below is divided by what is known about each SETD2-related condition.
Luscan-Lumish syndrome
Luscan-Lumish syndrome is a condition associated with SETD2 variants with or without macrocephaly and overgrowth.
Learning and Speech
People with SETD2 variants associated with Luscan-Lumish syndrome had developmental delay, intellectual disability, and speech delay or impairment.
- 15 out of 36 people had developmental delay (42 percent)
- 18 out of 36 people had intellectual disability (50 percent)
- 15 out of 36 people had speech delay or impairment (42 percent)
Behavior
People with Luscan-Lumish syndrome had behavioral issues, such as autism or features of autism, attention-deficit/hyperactivity disorder (ADHD), aggressive behavior, anxiety, and obsessive personality traits.
- 18 out of 35 people had autism (51 percent)
- 10 out of 35 people had ADHD (29 percent)
- 10 out of 35 people had other behavioral issues (29 percent)
- 5 out of 34 people had aggressive behavior (15 percent)
- 4 out of 34 people had anxiety (12 percent)
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Brain
People with Luscan-Lumish syndrome had a larger than average head size (macrocephaly), low muscle tone (hypotonia), seizures, or brain changes seen on magnetic resonance imaging (MRI).
- 24 out of 35 people had macrocephaly (69 percent)
- 7 out of 36 people had hypotonia (19 percent)
- 6 out of 35 people had seizures (17 percent)
- 4 out of 37 people had brain changes seen on MRI (11 percent)
Medical and physical concerns linked to Luscan-Lumish syndrome
Growth
About one-half of people with Luscan-Lumish syndrome were overgrown. Some people had obesity, tall height, long or large hands, a sideways curve of the spine (scoliosis), or were born with a heart defect. Obesity and tall height might normalize as a child ages. Bone age was often advanced.
- 18 out of 35 people were overgrown (51 percent)
- 12 out of 35 people had obesity (34 percent)
- 11 out of 35 people had tall height (31 percent)
- 5 out of 34 people had long or large hands (15 percent)
- 4 out of 34 people had scoliosis (12 percent)
- 5 out of 35 people were born with a heart defect (14 percent)
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Rabin-Pappas syndrome
Rabin-Pappas syndrome is a SETD2 condition associated with severe developmental delay and intellectual disability, hypotonia, feeding difficulties with failure to thrive, and a smaller than average head size (microcephaly). People tend to have the p.Arg1740Trp SETD2 variant. Other variants, such as p.Glu1718Lys and p.Asp2251Glu, were associated with Rabin-Pappas syndrome-like features.
Learning and Speech
People with SETD2 variants associated with Rabin-Pappas syndrome had developmental delay and intellectual disability, and they were unable to speak.
- 14 out of 14 people had developmental delay (100 percent)
- 14 out of 14 people had intellectual disability (100 percent)
- 14 out of 14 people were unable to speak (100 percent)
Brain
People with Rabin-Pappas syndrome had a smaller than average head size (microcephaly), low muscle tone (hypotonia), seizures, or brain changes seen on magnetic resonance imaging (MRI).
- 14 out of 14 people had microcephaly (100 percent)
- 14 out of 14 people had hypotonia (100 percent)
- 8 out of 14 people had seizures (57 percent)
- 12 out of 14 people had brain changes seen on MRI (86 percent)
Medical and physical concerns linked to Rabin-Pappas syndrome
Growth and development
Most people with Rabin-Pappas syndrome had failure to thrive, feeding difficulties, a sideways curve of the spine (scoliosis), a skeletal defect, and a heart or genitourinary defect. Many people had hearing issues and vision issues (for example, coats disease, optic nerve hypoplasia, glaucoma and/or cataracts).
- 12 out of 14 people had failure to thrive (86 percent)
- 13 out of 14 people had feeding difficulties (93 percent)
- 8 out of 14 people had scoliosis (57 percent)
- 14 out of 14 people had a skeletal defect (100 percent)
- 12 out of 14 people were born with a heart defect (86 percent)
- 12 out of 14 people had a genitourinary defect (86 percent)
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Facial changes
People with Rabin-Pappas syndrome tended to look different. Common facial features included eyes that are further apart, arched eyebrows, a broad bridge and tip of the nose, an undersized lower jaw, and a narrow opening of the eye lids.
Autosomal dominant intellectual developmental disorder-70 (MRD70)
Intellectual developmental disorder, autosomal dominant 70 is a SETD2 condition associated with mild to moderate developmental delay and intellectual disability, hypotonia, and behavioral issues. People tend to have the p.Arg1740Gln SETD2 variant.
Learning and Speech
People with SETD2 variants associated with autosomal dominant intellectual developmental disorder-70 had developmental delay, mild intellectual disability, and speech delay.
- 3 out of 3 people had developmental delay (100 percent)
- 3 out of 3 people had intellectual disability (100 percent)
- 3 out of 3 people had speech delay (100 percent)
Development
People with autosomal dominant intellectual developmental disorder-70 had low muscle tone (hypotonia) and/or skeletal defects.
- 2 out of 3 people had hypotonia (67 percent)
- 3 out of 4 people had skeletal defects (75 percent)
Where can I find support and resources?
Luscan-Lumish Syndrome SETD2 Family Support
Simons Searchlight
Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”
- Learn more about Simons Searchlight: www.simonssearchlight.org/frequently-asked-questions
- Simons Searchlight page on SETD2: www.simonssearchlight.org/research/what-we-study/setd2
- Simons Searchlight SETD2 Facebook page: Simons Searchlight SETD2 Facebook community
Sources and references
The content in this guide comes from published studies about SETD2-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.
- Orozco-Fernández, M., Peña-Vega, C. P., Anzola, L. K., & López, J. P. (2025). A previously unreported bilateral condylar hyperplasia as a manifestation of Luscan-Lumish syndrome. The Journal of Craniofacial Surgery, Epub ahead of print. doi:10.1097/scs.0000000000011872
- Pappas, J., & Rabin R. SETD2 neurodevelopmental disorders. 2022 Sep 22. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK575927/
- Parra, A., Rabin, R., Pappas, J., Pascual, P., Cazalla, M., Arias, P., Gallego-Zazo, N., Santana, A., Arroyo, I., … & Lapunzina, P. (2023). Clinical heterogeneity and different phenotypes in patients with SETD2 variants: 18 new patients and review of the literature. Genes (Basel), 14(6), 1179. doi:10.3390/genes14061179
- Ünsel-Bolat, G., Genç-Akdağ, D., & Bolat, H. (2026). Clinical insights into a rare SETD2 disorder: Report of a novel variant. Developmental Neurobiology, 86(1), e70002. doi:10.1002/dneu.70002
- Wójcik-Niklewska, B., & Filipek, E. (2025). Luscan-Lumish syndrome: A case report. World Journal of Clinical Cases, 13(18), 101471. doi:10.12998/wjcc.v13.i18.101471