HNRNPH2-Related Syndrome
HNRNPH2-related syndrome is also called Bain type of X-linked syndromic intellectual disability and HNRNPH2-related neurodevelopmental disorder. For this webpage, we will be using the name HNRNPH2-related syndrome to encompass the wide range of variants observed in the people identified.
What is HNRNPH2-related syndrome?
HNRNPH2-related syndrome happens when there are changes in the HNRNPH2 gene. These changes can keep the gene from working as it should.
The HNRNPH2 gene is located on the X chromosome, which is one of the sex chromosomes.
Key Role
The HNRNPH2 gene plays an important role in processing messenger RNA, also called mRNA, which cells use to make proteins.
Symptoms
Because the HNRNPH2 gene is important for brain activity, many people who have HNRNPH2-related syndrome have:
- Developmental delay
- Intellectual disability
- Seizures
- Speech and language difficulties
- Autism
- Abnormal muscle tone
- Movement issues
- Attention-deficit/hyperactivity disorder (ADHD)
- Aggression
- Anxiety
- Feeding issues and constipation
- Brain changes seen on magnetic resonance imaging (MRI) for some people
What causes HNRNPH2-related syndrome?
HNRNPH2-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 HNRNPH2 gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways.
X-linked dominant conditions
HNRNPH2-related syndrome usually results from a spontaneous variant in the HNRNPH2 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 HNRNPH2 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 HNRNPH2 gene variant found in their child who has the syndrome. Rarely, HNRNPH2-related syndrome is inherited.
X-Linked Dominant Genetic Syndrome
Why does my child have a change in the HNRNPH2 gene?
No parent causes their child’s HNRNPH2-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 HNRNPH2-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 HNRNPH2-related syndrome depends on the genes of both biological parents.
- For a biological female parent who does not have 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 increased 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.
- For a biological female parent who has the same HNRNPH2 variant and is pregnant with a daughter, there is 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 without the same HNRNPH2 genetic variant.
- If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.
For a symptom-free brother or sister of someone who has HNRNPH2-related syndrome, the sibling’s risk of having a child who has HNRNPH2-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing HNRNPH2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit HNRNPH2-related syndrome.
- If the biological mother has the same genetic variant causing HNRNPH2-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has HNRNPH2-related syndrome is 50 percent.
For a person who has HNRNPH2-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have HNRNPH2-related syndrome?
As of 2025, about 67 people with HNRNPH2-related syndrome have been identified in medical research.
Do people who have HNRNPH2-related syndrome look different?
People who have HNRNPH2-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- Short height
- Difficulty gaining weight
- Smaller than average head size
- Wide-set eyes
- Full and wide lips
- Sideways curve of the spine, also called scoliosis
How is HNRNPH2-related syndrome treated?
Scientists and doctors have only just begun to study HNRNPH2-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 HNRNPH2-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 HNRNPH2-related syndrome
Females who carry a pathogenic or likely pathogenic HNRNPH2 variant usually have medical features. Researchers have identified one female parent who carried the same HNRNPH2 variant as their child. They were expected to not have the condition due to X chromosome inactivation. This is a random process where a cell chooses one X chromosome to silence gene expression. If the affected X chromosome is inactivated, this means that the HNRNPH2 variant would be silenced or turned off.
Males with a pathogenic or likely pathogenic HNRNPH2 variant have medical features. The information below includes both females and males with HNRNPH2-related syndrome.
Speech and learning
All people with HNRNPH2-related syndrome had global developmental delay and/or intellectual disabilities, usually moderate to severe. Most people had speech issues. Some were able to speak only a few words and some were non-verbal.
- 46 out of 46 people had global developmental delay and/or intellectual disability (100 percent)
- 37 out of 45 people had speech issues (82 percent)
Behavior
Some people with HNRNPH2-related syndrome had behavioral issues, such as autism, anxiety, self-injury behavior, and attention-deficit/hyperactivity disorder (ADHD).
- 32 out of 42 people had behavioral issues (76 percent)
Brain
People with HNRNPH2-related syndrome had low muscle tone (hypotonia) or high muscle tone (hypertonia), seizures, and a smaller than average head size (microcephaly). Common seizure types were staring episodes and tonic–clonic seizures. The average age of seizure onset was about 9 years old. Most people had normal brain magnetic resonance imaging (MRI).
- 41 out of 46 people had hypotonia (89 percent)
- 18 out of 46 people had seizures (39 percent)
- 16 out of 44 people had microcephaly (36 percent)
Medical and physical concerns linked to HNRNPH2-related syndrome
Mobility
People with HNRNPH2-related syndrome had a movement disorder, such as motor planning issues, a loss of muscle coordination and balance (ataxia), clumsiness, stereotypic behavior, and abnormal walking.
Feeding and gastrointestinal issues
Most people with HNRNPH2-related syndrome had feeding challenges and constipation. Other issues were poor appetite, gastrointestinal problems like feeding difficulties (GERD), swallowing issues, diarrhea, overeating, and eating things that are not considered food.
- 28 out of 41 people had feeding and gastrointestinal issues (68 percent)
Growth
About one-half of people had difficulty gaining weight, which was likely a result of feeding issues. Some people were shorter than average and had a smaller than average head size. Some people with HNRNPH2-related syndrome had orthopedic issues, including flat feet; a sideways curve of the spine, also called scoliosis; hip dysplasia; and fingers that were long, thin, and curved.
- 6 out of 33 people were short for their age (18 percent)
- 25 out of 37 people had orthopedic issues (68 percent)
Other medical features
People with HNRNPH2-related syndrome had vision issues, most often strabismus (crossed eyes); hearing loss; and sleep challenges, such as falling asleep and staying asleep.
- 29 out of 43 people had vision issues (67 percent)
- 16 out of 41 people had sleep challenges (39 percent)
Where can I find support and resources?
Yellow Brick Road Project
The Yellow Brick Road Project is a charitable foundation whose mission is to fund research to identify, understand, treat, and ultimately cure those impacted by HNRNPH2 mutations. We do this by funding initiatives to identify more individuals with HNRNPH2 mutations, connecting families impacted by HNRNPH2 in order to contribute to the understanding of the disorder, raising awareness of HNRNPH2 mutations in the general public and scientific communities, and by funding research into HNRNPH2 mutations.
To Cure a Rose Foundation
To Cure a Rose Foundation brings genetic treatments to children with debilitating rare diseases, many associated with autism. They are focused on funding and bringing together determined researchers and promising technology to create a brighter future for children.
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 HNRNPH2 – www.simonssearchlight.org/research/what-we-study/hnrnph2
- Simons Searchlight HNRNPH2 Facebook community – https://www.facebook.com/groups/hnrnph2
Sources and References
The content in this guide comes from a published study about HNRNPH2-related syndrome. Below you can find details about the study.
- Davis, T. J., Salazar, R., Beenders, S., Boehme, A., LaMarca, N. M., & Bain, J. M. (2024). A prospective, longitudinal study of caregiver-reported adaptive skills and function of individuals with HNRNPH2-related neurodevelopmental disorder. Advances in Neurodevelopmental Disorders, 8(3), 445-456. https://link.springer.com/article/10.1007/s41252-023-00346-1
- Madhok, S., Bain, J., Adam, M. P., Feldman, J., Mirzaa, G. M., Pagon, R. A., Wallace, S. E., & Amemiya, A. HNRNPH2-related neurodevelopmental disorder. 2022 Sep 15. 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/NBK584018/