What is ASH1L-related syndrome?

ASH1L-related syndrome occurs when there are changes to the ASH1L gene that keep it from working as expected.

 

Key role: ASHL1 plays an important role in brain development. It is particularly important in regulating the activity of other genes.

 

Symptoms: ASH1L-related syndrome can have mild to severe effects on the development of communication, social and learning skills. It can affect how a person acts or interacts with others.

 

Because the ASH1L gene is important in brain development, many individuals with ASH1Lrelated syndrome have:

• Speech delay

• Intellectual disability

• Learning difficulties

What causes ASH1L-related syndrome?

Our genes contain the instructions, or code, that tell our cells how to grow, develop and work. A change in the genetic code can lead to physical and/or developmental issues. Every child gets two copies of the ASH1L gene: one from the mother, via the egg, and one from the father, via the sperm. In most cases, parents pass on exact copies of genes to their child. But the process of copying DNA is not perfect. Sometimes a random change occurs in the sperm or egg. This change to the genetic code is considered a de novo (new) change.

 

De novo changes can occur in any gene. Indeed, everyone has a handful of de novo changes, most of which don’t affect our health. But because ASH1L plays an important role in development, de novo changes in this gene can have a meaningful impact on an individual. Research shows that ASH1L-related syndrome is often the result of a de novo change in ASHL1. Many parents who have been genetically tested do not carry the gene change found in their child with the syndrome.

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Why does this happen?

No parent causes their child’s ASH1L-related syndrome, because no parent has any control over the genetic changes that they do or do not pass on to their children. It is important to remember that nothing a parent does before or during the pregnancy causes this to happen. The genetic change takes place on its own and cannot be predicted or prevented.

Can it happen in my family again?

Each family situation is different. A clinical geneticist or genetic counselor can give you specific advice on the chance that this will happen again in your family. For the biological parent of a child with ASH1L-related syndrome, the risk of having another child with ASH1L-related syndrome depends on their genes and the other parent’s genes.

 

• The chance of having another child with ASH1L-related syndrome is on average 1 percent if neither parent has the same gene change as their child with the syndrome. This chance is higher than that for the general population. The increase in risk is due to the very unlikely possibility that more of the mother’s egg cells or the father’s sperm cells carry the same genetic change.

• The chance of having another child with ASH1L-related syndrome is 50 percent if either parent has the same change in the ASH1L gene as their child with the syndrome.

 

For a symptom-free sibling of an individual with ASH1L-related syndrome, the risk of having a child with ASH1L-related syndrome depends on the symptom-free sibling’s genes and their parents’ genes.

• If neither parent has the same gene change found in their child with the syndrome, the symptom-free sibling has a nearly zero chance of having a child with ASH1L-related syndrome.

• If one of the parents has the same gene change found in their child with the syndrome, the symptom-free sibling has up to a 50 percent chance of also having the same gene change. If the symptom-free sibling has the same gene change as their sibling with the syndrome, their chance of having a child with ASH1L-related syndrome is 50 percent.

 

For an individual with ASH1L-related syndrome, the risk of having a child with ASH1L-related syndrome is approximately 50 percent

Do people with ASH1L-related syndrome look different?

People with ASH1L-related syndrome generally do not look very different from others.

How is ASH1L-related syndrome treated?

Scientists and doctors have only just begun to study ASH1L-related syndrome. At this point, there are no medicines designed to treat the condition. However, a genetic diagnosis can help individuals choose the most appropriate monitoring and therapies. A doctor may refer the individual to specialists for:

• Physical exam including an evaluation of the brain

• Genetics consultation

• Developmental/behavioral evaluation

The individual can be followed over time by a developmental pediatrician, neurologist or psychologist. This specialist can help:

• Recommend the right therapies (for example, physical therapy, occupational therapy, speech therapy, behavioral therapy)

• Guide individualized education plans (IEPs)

Specialists recommend that therapies for ASH1L-related syndrome begin as early as possible, ideally before the child begins school. A doctor may also refer the individual to other specialists as needed.

ASH1L-related syndrome is extremely rare. Doctors and scientists have just recently begun to study the condition. As of 2019, research studies have described approximately 20 people with the syndrome. The information that follows summarizes information from research on this small group, highlighting how many people have different symptoms. See the Sources and references section for a full list of articles

Behavioral and developmental concerns linked to ASH1L-related syndrome

Behavior: Most people with ASHL1-related syndrome have behavioral symptoms, including autism, ADHD and obsessive behaviors. Five reported sleep problems, including excessive daytime sleepiness and sleep apnea.

 

Speech: Nearly 40 percent of people with the condition have speech delays, which vary in severity.

 

Learning: Everyone identified so far with ASH1L-related syndrome has some level of intellectual disability, ranging from mild to severe.

Medical and physical concerns linked to ASH1L-related syndrome

Brain: Nearly a quarter of people with ASH1L-related syndrome have seizures.

 

Motor concerns: Thirty percent of people with the condition have motor delays.

 

Feeding and GI issues: Thirty percent have GI issues, including constipation.

 

Congenital anomalies: Some individuals report congenital anomalies, including increased distance between eyes and failure of testes to descend.

Summary of medical concerns:

• 11/13 have behavioral symptoms, including autism, ADHD and obsessive behaviors

• 5/13 have speech delay

• 13/13 have intellectual disability

• 4/13 motor delay

• 4/13 have GI issues

Sources and References

The information in this guide is drawn from published medical articles about ASH1L-related syndrome. Below is a list of the lead authors’ names, where and when their articles were published, the articles’ titles and the URLs where summaries (abstracts) or, in some cases, the full article can be found online.

 

Shen W. et al. Eur. J. Med. Genet. 62, 55-60 (2019) De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder, www.ncbi.nlm.nih.gov/pubmed/29753921.

 

Okamoto N. et al. Am. J. Med. Genet. A 173, 1644-1648 (2017) Novel MCA/ID syndrome with ASH1L mutation, https://www.ncbi.nlm.nih.gov/pubmed/28394464.