USP9X-Related Syndrome
USP9X-related syndrome is also called intellectual developmental disorder, X-linked 99. For this webpage, we will be using the name USP9X-related syndrome to encompass the wide range of variants observed in the people identified.
What is USP9X-related syndrome?
USP9X-related syndrome happens when there are changes in the USP9X gene. These changes can keep the gene from working as it should.
Key Role
The USP9X gene plays a key role in early growth of the brain.
Symptoms
Because the USP9X gene is important for brain activity, many people who have USP9X-related syndrome have:
- Intellectual disability
- Short height
- Language impairment
- Brain changes seen on magnetic resonance imaging (MRI)
- Feeding difficulties
What causes USP9X-related syndrome?
USP9X-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’s egg, and one copy from the father’s 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 USP9X gene is located on the X chromosome, therefore 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 USP9X-related syndrome.
Biological females who have variants in this gene may or may not have symptoms of USP9X-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
USP9X-related syndrome usually results from a spontaneous variant in the USP9X 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 USP9X 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 USP9X gene variant found in their child who has the syndrome.
In some cases, USP9X-related syndrome is inherited. Biological females who inherit the USP9X gene variant tend to have milder symptoms than those who have a de novo variant.
X-linked recessive conditions
Research shows that USP9X-related syndrome is often the result of an inherited variant in USP9X. This means that USP9X-related syndrome happens because the genetic variant was passed down from a biological female parent. Biological females that carry the USP9X variant usually do not have symptoms, but sometimes they might.
Sometimes it results from a spontaneous variant in the USP9X 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.
Biological females who have variants in this gene may or may not have symptoms of USP9X-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 Genetic Syndrome
X-Linked Recessive Genetic Syndrome
No parent causes their child’s USP9X-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 foreseen or stopped.
What are the chances that other family members of future children will have USP9X-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 USP9X-related syndrome depends on the genes of both biological parents.
- Biological females who have a variant in the USP9X 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 USP9X-related syndrome, the sibling’s risk of having a child who has USP9X-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing USP9X-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit USP9X-related syndrome.
- If the biological mother has the same genetic variant causing USP9X-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has USP9X-related syndrome is 50 percent.
For a person who has USP9X-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have USP9X-related syndrome?
As of 2024, at least 110 people with USP9X-related syndrome have been identified in a medical clinic.
Do people who have USP9X-related syndrome look different?
People who have USP9X-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- Changes in the teeth
- Sideways curve of the spine, also called scoliosis
- Extra fingers
How is USP9X-related syndrome treated?
Scientists and doctors have only just begun to study USP9X-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 USP9X-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/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 USP9X-related syndrome
The USP9X gene is on the X chromosome, which is one of the sex chromosomes. USP9X-related syndrome is more common in females than males. Pathogenic or likely pathogenic variants in USP9X affect females and males differently.
Females with USP9X-related syndrome
Females with USP9X-related syndrome usually had a loss-of-function genetic variant that was brand new (de novo), meaning not inherited.
Speech and learning
Females with USP9X-related syndrome had developmental delays, intellectual disabilities, and language impairments.
- 38 out of 39 people had developmental delay or intellectual disability (97 percent)
Brain
Some females with USP9X-related syndrome had seizures, lower than average muscle tone (hypotonia), and brain changes seen on magnetic resonance imaging (MRI), such as a decrease in the volume of the corpus callosum or cerebellum, abnormal folding patterns of the brain, and enlarged ventricles of the brain.
- 4 out of 34 people had seizures (12 percent)
- 8 out of 35 people had hypotonia (23 percent)
Other features
It was common for females with USP9X-related syndrome to have teeth findings, vision issues, and hearing loss. Sometimes they had other features, such as feeding difficulties, and thyroid defects. Females also had body structure changes, including heart and finger defects and narrowing of the back of the nasal cavity (choanal atresia).
- 23 out of 36 people had teeth findings (64 percent)
- 25 out of 36 people had vision issues (69 percent)
- 21 out of 36 people had hearing loss (58 percent)
Males with USP9X-related syndrome
Males with USP9X-related syndrome usually had missense variants in the USP9X gene that resulted in a partial loss of the USP9X protein. Males might have inherited their variant from their unaffected mother, or their variant might have been brand new (de novo).
Speech and learning
All males with USP9X-related syndrome had developmental delays and intellectual disabilities. Many people had speech delay and language issues.
- 19 out of 19 people had intellectual disability (100 percent)
- 11 out of 15 people had speech delay and language issues (73 percent)
Behavior
Males with USP9X-related syndrome had behavioral issues, such as autism, anxiety, attention issues, obsession, or aggression.
- 10 out of 13 people had behavioral issues (77 percent)
Brain
Some males with USP9X-related syndrome had seizures, lower than average muscle tone (hypotonia) or motor issues, and brain changes seen on magnetic resonance imaging (MRI).
- 3 out of 17 people had seizures (18 percent)
- 17 out of 17 people had hypotonia or motor issues (100 percent)
- 14 out of 14 people had brain changes seen on MRI (100 percent)
Other medical issues
Males with USP9X-related syndrome had growth issues; gastrointestinal findings, such as gastroesophageal reflux or constipation; skin and hair defects; and visual difficulties. Two males were born with heart defects.
- 8 out of 17 people had growth issues (47 percent)
- 15 out of 19 people had gastrointestinal findings (79 percent)
- 9 out of 13 people had skin and hair defects (69 percent)
- 9 out of 13 people had visual difficulties (69 percent)
Where can I find support and resources?
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 USP9X: www.simonssearchlight.org/research/what-we-study/usp9x
- Simons Searchlight USP9X Facebook community: https://www.facebook.com/groups/usp9x
Sources and References
The content in this guide comes from published studies about USP9X-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.
- Agazzi, C., Magliozzi, M., Iacoviello, O., Palladino, S., Delvecchio, M., Masciopinto, M., Galati, A., Novelli, A., Causio, F. A., … & Fischetto, R. (2023). Novel variant in the USP9X gene is associated with congenital heart disease in a male patient: A case report and literature review. Molecular Syndromology, 14(2), 158-163. https://pubmed.ncbi.nlm.nih.gov/37064340/
- De Laurentiis, A., Ciaccio, C., Erbetta, A., Pinelli, M., Nigro, V., Pantaleoni, C., & D’Arrigo, S. (2023). Periventricular heterotopia in a male child with USP9X missense variant. American Journal of Medical Genetics Part A, 191(5), 1350-1354. https://pubmed.ncbi.nlm.nih.gov/36680497/
- Li, D., March, M. E., Wang, T., Merengwa, V., Sertori Finoti, L., Schrier Vergano, S. A., Hakonarson, H., & Bhoj, E. J. (2022). Exome and RNA-Seq analyses of an incomplete penetrance variant in USP9X in female-specific syndromic intellectual disability. American Journal of Medical Genetics Part A, 188(6), 1808-1814. https://pubmed.ncbi.nlm.nih.gov/35253988/
- Meira, J. G. C., Magalhães, B. S., Ferreira, I. B. B., Tavares, D. F., Kobayashi, G. S., & Leão, E. (2021). Novel USP9X variant associated with syndromic intellectual disability in a female: A case study and review. American Journal of Medical Genetics Part A, 185(5), 1569-1574. https://pubmed.ncbi.nlm.nih.gov/33638286/