HECW2-Related Syndrome
HECW2-related syndrome is also called neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL). For this webpage, we will be using the name HECW2-related syndrome to encompass the wide range of variants observed in the people identified.
What is HECW2-related syndrome?
HECW2-related syndrome happens when there are changes in the HECW2 gene. These changes can keep the gene from working as it should. The HECW2 gene is also called NEDL2.
Key Role
HECW2 plays a role in the communication between cells in the brain.
Symptoms
Because the HECW2 gene is important for brain activity, many people who have HECW2-related syndrome have:
- Developmental delays
- Intellectual disability
- Low muscle tone
- Autism spectrum disorder
- Speech issues
- Eye problems, such as optic neuropathy, cortical visual impairment, and ocular movement disorders
- Gastrointestinal problems, such as trouble swallowing, problems with digestion, acid reflux, and constipation
- Epilepsy
- Brain changes observed on magnetic resonance imaging (MRI)
What causes HECW2-related syndrome?
HECW2-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 HECW2 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 HECW2 plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that HECW2-related syndrome is often the result of a de novo variant in HECW2. Many parents who have had their genes tested do not have the HECW2 genetic variant found in their child who has the syndrome. In some cases, HECW2-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
HECW2-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in HECW2 they will likely have symptoms of HECW2-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 HECW2 gene?
No parent causes their child’s HECW2-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 HECW2-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 HECW2-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 HECW2-related syndrome, the sibling’s risk of having a child who has HECW2-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing HECW2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit HECW2-related syndrome.
How many people have HECW2-related syndrome?
As of 2024, over 38 people with HECW2-related syndrome have been identified in a medical clinic.
Do people who have HECW2-related syndrome look different?
People who have HECW2-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- Forehead that sticks out
- Bridge of the nose that sticks out
- Deep-set eyes
- Concave-shaped face
- Roof of mouth with a high arch
How is HECW2-related syndrome treated?
Scientists and doctors have only just begun to study HECW2-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 HECW2-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 HECW2-related syndrome
Speech and Learning
All people with HECW2-related syndrome had developmental delay or intellectual disability, and many people were non-verbal.
- 33 out of 33 people had developmental delay or intellectual disability (100 percent)
- 12 out of 16 people were non-verbal (75 percent)
Behavior
Behavioral issues occurred in people with HECW2-related syndrome, including autism spectrum disorder, repetitive and stereotypic behaviors, and/or self-injury.
- 29 out of 33 people had behavioral issues (89 percent)
- 5 out of 22 people had autism (23 percent)
Brain
Many people with HECW2-related syndrome had seizures and/or brain changes observed on magnetic resonance imaging (MRI). Brain changes included having regions that are smaller than average, as well as enlarged or increased fluid spaces. All people had low muscle tone (hypotonia).
- 20 out of 33 people had seizures (61 percent)
- 18 out of 33 people had brain changes on MRI (55 percent)
- 33 out of 33 people had hypotonia (100 percent)
Medical and physical concerns linked to HECW2-related syndrome
Vision
Vision issues were common for people with HECW2-related syndrome, such as optic neuropathy, cortical visual impairment (CVI), and ocular movement disorders.
- 28 out of 33 people had vision issues (85 percent)
Gastrointestinal issues
Many people had dysmotility (muscles of the digestive system that have issues with moving food through the digestive system) and/or difficulty swallowing. Symptoms appeared as gastroesophageal reflux disease (GERD), gastroparesis, and constipation. Eight people required a gastrostomy tube (G-tube) for feeding.
- 23 out of 33 people had gastrointestinal issues (70 percent)
Sleep
About one-half of people had sleep issues, most often insomnia.
- 14 out of 33 people had difficulty with sleep (43 percent)
Skeletal issues
Some people with HECW2-related syndrome had skeletal defects, such as decreased bone mineralization, pectus excavatum (sunken chest bone), pes planus (flat feet), and brachydactyly of the hands and feet (shorter than average fingers or toes).
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 HECW2 – www.simonssearchlight.org/research/what-we-study/hecw2
- Simons Searchlight HECW2 Facebook community – https://www.facebook.com/groups/hecw2
Sources and References
The content in this guide comes from a published study about HECW2-related syndrome. Below you can find details about the study, as well as a link to the full article.
- Acharya, A., Kavus, H., Dunn, P., Nasir, A., Folk, L., Withrow, K., Wentzensen, I. M., Ruzhnikov, M. R. Z., Fallot, C., … & Schrauwen, I. (2022). Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders. Journal of Medical Genetics, 59(7), 669-677. https://pubmed.ncbi.nlm.nih.gov/34321324/
- Krami, A. M., Bouzidi, A., Charif, M., Amalou, G., Charoute, H., Rouba, H., Roky, R., Lenaers, G., Barakat, A., & Nahili, H. (2022). A homozygous nonsense HECW2 variant is associated with neurodevelopmental delay and intellectual disability. European Journal of Medical Genetics, 65(6), 104515. https://pubmed.ncbi.nlm.nih.gov/35487419/
- Yanagishita, T., Hirade, T., Shimojima Yamamoto, K., Funatsuka, M., Miyamoto, Y., Maeda, M., Yanagi, K., Kaname, T., Nagata, S., … & Yamamoto, T. (2021). HECW2-related disorder in four Japanese patients. American Journal of Medical Genetics Part A, 185(10), 2895-2902. https://pubmed.ncbi.nlm.nih.gov/34047014/ [correction:https://pubmed.ncbi.nlm.nih.gov/34245093/]