DDX3X-Related Syndrome
DDX3X-related syndrome is also called intellectual developmental disorder, X-linked syndromic, Snijders Blok type, orDDX3X neurodevelopmental disorder. For this webpage, we will be using the name DDX3X-related syndrome to encompass the wide range of variants observed in the people identified.
What is DDX3X-related syndrome?
DDX3X-related syndrome happens when there are changes in the DDX3X gene. These changes can keep the gene from working as it should.
Key Role
DDX3X plays a key role in the growth of the brain.
Symptoms
Because the DDX3X gene is important for brain activity, many people who have DDX3X-related syndrome have:
- Developmental delay
- Intellectual disability
- Changes in muscle tone
- Movement disorders
- Vision impairments
- Autism
- Attention-deficit/hyperactivity disorder (ADHD)
- Language impairment
- Heart defects
- Brain changes seen on magnetic resonance imaging (MRI)
What causes DDX3X-related syndrome?
DDX3X-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. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother, from the egg, and one copy from the father, from the sperm.
We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father.
In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both.
The DDX3X gene is located on the X chromosome, so variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have DDX3X-related syndrome.
Biological females who have variants in this gene may or may not have symptoms of DDX3X-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.
X-linked dominant conditions
DDX3X-related syndrome usually results from a spontaneous variant in the DDX3X gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene 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 DDX3X plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the DDX3X gene variant found in their child who has the syndrome.
In some cases, DDX3X-related syndrome is inherited. Biological females who inherit the DDX3X gene variant tend to have milder symptoms than those who have a de novo variant.
X-linked recessive conditions
Research shows that DDX3X-related syndrome is often the result of an inherited variant in DDX3X. This means that DDX3X-related syndrome happens because the genetic variant was passed down from a biological female parent. Biological females that carry the DDX3X variant usually do not have symptoms, but sometimes they might.
Sometimes it results from a spontaneous variant in the DDX3X gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant.
X-Linked Dominant Genetic Syndrome
X-Linked Recessive Genetic Syndrome
Why does my child have a change in the DDX3X gene?
No parent causes their child’s DDX3X-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 of future children will have DDX3X-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 DDX3X-related syndrome depends on the genes of both biological parents.
- Biological females who have a variant in the DDX3X gene and are pregnant with a daughter have a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene.
- If they are pregnant with a son, the child has a 50 percent chance of inheriting the genetic variant and the syndrome.
For a symptom-free brother or sister of someone who has DDX3X-related syndrome, the sibling’s risk of having a child who has DDX3X-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing DDX3X-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit DDX3X-related syndrome.
- If the biological mother has the same genetic variant causing DDX3X-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has DDX3X-related syndrome is 50 percent.
For a person who has DDX3X-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have DDX3X-related syndrome?
As of 2025, over 230 people with DDX3X-related syndrome have been described in medical research.
Do people who have de novo changes in the DDX3X look different?
People who have DDX3X-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- Smaller than average head size
- Thin upper lip
- Large ears
How is DDX3X-related syndrome treated?
Scientists and doctors have only just begun to study DDX3X-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:
- 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:
- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for DDX3X-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: epilepsy.com/…t-is-epilepsy/seizure-types
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 DDX3X-related syndrome
The DDX3X gene is located on the X chromosome, and damaging genetic variants cause DDX3X-related syndrome in males and females.
Females with DDX3X-related syndrome are identified more often than males with the syndrome.
Mothers of sons with a DDX3X variant are not affected or have some medical features.
Learning and speech
Most females with DDX3X-related syndrome had developmental delay or intellectual disability, and speech delay or impairment.
- 228 out of 230 people had developmental delay (99 percent)
- 224 out of 230 people had intellectual disability (97 percent)
Behavior
Many females with DDX3X-related syndrome had behavioral issues, such as autism, attention-deficit/hyperactivity disorder (ADHD), self-injury behavior, and aggression.
- 38 out of 140 people had autism (27 percent)
- 30 out of 134 people had ADHD (22 percent)
Brain
Females with DDX3X-related syndrome had neurological medical issues, such as a smaller than average head size (microcephaly), seizures, brain changes seen on magnetic resonance imaging (MRI), lower than average muscle tone (hypotonia), higher than average muscle tone (hypertonia), and movement challenges.
- 52 out of 178 people had microcephaly (29 percent)
- 35 out of 164 people had seizures (21 percent)
- 135 out of 163 people had brain changes seen on MRI (83 percent)
- 152 out of 199 people had hypotonia (76 percent)
- 43 out of 128 people had hypertonia (34 percent)
- 64 out of 97 people had movement challenges (66 percent)
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Medical and physical concerns linked to DDX3X-related syndrome in females
Vision and hearing issues
Females with DDX3X-related syndrome had vision issues, such as crossed eyes (strabismus) and eyes that move rapidly without control (nystagmus). Some people had hearing and/or ear defects.
- 81 out of 196 people had vision issues (41 percent)
- 13 out of 160 people had hearing and/or ear defects (8 percent)
Other developmental features
Females with DDX3X-related syndrome had recurrent infections, a sideways curve of the spine (scoliosis), heart findings, gastrointestinal issues, and early puberty onset.
- 14 out of 29 people had recurrent infections (48 percent)
- 24 out of 162 people had scoliosis (15 percent)
- 21 out of 131 people had heart findings (16 percent)
- 24 out of 29 people had gastrointestinal issues (83 percent)
- 17 out of 147 people had early puberty onset (12 percent)
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Males with DDX3X-related syndrome
Learning and speech
Males with DDX3X-related syndrome had developmental delay or intellectual disability, and all had speech delay and/or language impairment.
- 31 out of 31 people had developmental delay (100 percent)
- 26 out of 28 people had intellectual disability (93 percent)
- 24 out of 24 people had speech delay and/or language impairment (100 percent)
The severity of intellectual disability (ID) varied among people:
- 4 out of 23 people had severe ID (17 percent)
- 2 out of 23 people had moderate to severe ID (10 percent)
- 6 out of 23 people had moderate ID (26 percent)
- 7 out of 23 people had mild ID (30 percent)
- 4 out of 23 people had unknown level of ID (17 percent)
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Behavior
Males with DDX3X-related syndrome had behavioral issues, such as autism and attention-deficit/hyperactivity disorder (ADHD).
- 22 out of 28 people had behavioral issues (79 percent)
- 8 out of 22 people had autism (36 percent)
- 5 out of 19 people had ADHD (26 percent)
Brain
Males with DDX3X-related syndrome had neurological medical issues, such as a smaller than average head size (microcephaly), a larger than average head size (macrocephaly), seizures, brain changes seen on magnetic resonance imaging (MRI), lower than average muscle tone (hypotonia), higher than average muscle tone (hypertonia), and movement challenges.
- 4 out of 28 people had microcephaly (14 percent)
- 3 out of 28 people had macrocephaly (11 percent)
- 2 out of 23 people had seizures (9 percent)
- 16 out of 22 people had brain changes seen on MRI (73 percent)
- 15 out of 23 people had hypotonia (65 percent)
- 4 out of 15 people had hypertonia (27 percent)
- 19 out of 25 people had movement challenges (76 percent)
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Medical and physical concerns linked to DDX3X-related syndrome in males
Vision and hearing issues
Males with DDX3X-related syndrome had crossed eyes (strabismus), other vision issues, conductive hearing loss, or hearing and/or ear defects.
- 7 out of 28 people had strabismus (25 percent)
- 16 out of 28 people had other vision issues (57 percent)
- 5 out of 25 people had conductive hearing loss (20 percent)
- 13 out of 25 people had hearing and/or ear defects (52 percent)
Other developmental features
Males with DDX3X-related syndrome had recurrent ear infections, skeletal defects, heart findings, gastrointestinal issues, and urogenital issues.
- 11 out of 25 people had recurrent ear infections (44 percent)
- 6 out of 17 people had skeletal defects (35 percent)
- 8 out of 26 people had heart findings (31 percent)
- 13 out of 22 people had gastrointestinal issues (59 percent)
- 9 out of 22 people had urogenital issues (41 percent)
Where can I find support and resources?
DDX3X Foundation
The mission of the DDX3X Foundation is to connect families, resources, and the medical community to advance research for a treatment or cure to DDX3X Syndrome. Their ultimate goal is to accelerate brain function in individuals affected by DDX3X Syndrome through advances in cell and gene therapy and pharmaceuticals.
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 webpage with more information on DDX3X – www.simonssearchlight.org/research/what-we-study/deaf1
- Simons Searchlight DDX3X Facebook community– https://www.facebook.com/groups/ddx3x
Sources and References
- Johnson-Kerner, B., Snijders Blok, L., Suit, L., Thomas, J., Kleefstra, T., & Sherr, E. H. DDX3X-related neurodevelopmental disorder. 2020 Aug 27. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK561282/
- Kennis, M. G. P., Rots, D., Bouman, A., Ockeloen, C. W., Boelen, C., Marcelis, C. L. M., de Vries, B. B. A., Elting, M. W., Waisfisz, Q., … & Snijders Blok, L. (2025). DDX3X-related neurodevelopmental disorder in males – presenting a new cohort of 19 males and a literature review. European Journal of Human Genetics, 33(8), 980-988. doi:10.1038/s41431-025-01832-x
- Parra, A., Pascual, P., Cazalla, M., Arias, P., Gallego-Zazo, N., San-Martín, E. A., Silván, C., Santos-Simarro, F., Nevado, J., … & Lapunzina, P. (2024). Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder. Clinical Genetics, 105(2), 140-149. doi:10.1111/cge.14440
- Ruault, V., Burger, P., Gradels-Hauguel, J., Ruiz, N., Jamra, R. A., Afenjar, A., Alembik, Y., Alessandri, J. L., Arpin, S., … & Geneviève, D. (2024). Lessons from two series by physicians and caregivers’ self-reported data in DDX3X-related disorders. Molecular Genetics & Genomic Medicine, 12(1), e2363. doi:10.1002/mgg3.2363