GENE GUIDE

ADNP-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has ADNP-Related Syndrome.
a doctor sees a patient

ADNP-related syndrome is also called Helsmoortel-Van der Aa syndrome. For this webpage, we will be using the name ADNP-related syndrome to encompass the wide range of variants observed in the people identified.

ADNP-related syndrome happens when there are changes to the ADNP gene. These changes can keep the gene from working as it should.

Key role

The ADNP gene plays a key role in the brain and body, including the heart and intestines.

Symptoms

Because the ADNP gene is important in the development and function of brain cells, many people who have ADNP-related syndrome have:

  • Developmental delay, or intellectual disability, or both
  • Speech and language delay
  • Autism or symptoms of autism
  • Other behavior issues (anxiety, ADHD, OCD, aggressive behavior)
  • Distinctive facial features
  • Heart problems
  • Vision problems like farsightedness or crossed eyes
  • Sleep difficulties
  • Seizures
  • Musculoskeletal problems (joint laxity, hand and foot defects, etc.)
  • Motor delay
  • Endocrine issues
  • Renal problems
  • Hearing loss
  • Recurrent infections
  • High pain tolerance
  • Gastrointestinal problems like feeding difficulties, GERD, constipation

ADNP-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 ADNP 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 ADNP plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that ADNP-related syndrome is often the result of a de novo variant in ADNP. Many parents who have had their genes tested do not have the ADNP genetic variant found in their child who has the syndrome. In some cases, ADNP-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

ADNP-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in ADNP they will likely have symptoms of ADNP-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

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

Why does my child have a change in the ADNP gene?

No parent causes their child’s ADNP-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.

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 ADNP-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 ADNP-related syndrome, the sibling’s risk of having a child who has ADNP-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing ADNP-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit ADNP-related syndrome. 
  • If one biological parent has the same genetic variant causing ADNP-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent.

For a person who has ADNP-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 133 people with ADNP-related syndrome have been identified in a medical clinic.

People who have ADNP-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Enlarged forehead and high hairline
  • Wide bridge of nose
  • Cup-shaped ears that stick out and small, low-set ears
  • Changes in the appearance of hands, including extra fingers, also called polydactyly
  • Downslanted palpebral fissures of the eyes
  • Noticeable eyelashes
  • Widely spaced teeth
  • Thin vermilion of the upper lip, pointed chin
  • Short nose with full, upturned nasal tip
  • Long philtrum, which is the groove between the base of the nose and the upper lip

Scientists and doctors have only just begun to study ADNP-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 ADNP-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

Most people with ADNP-related syndrome have autism (67 percent) or symptoms of autism. Some people who have the syndrome also have anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention deficit hyperactivity disorder, also called ADHD, and sleep problems.

Speech

Almost everyone who has the syndrome has speech delay. Children are often late to start talking and may have a limited vocabulary.

Learning

Most people have some level of intellectual disability, ranging from mild to severe, and will need special educational support.

  • 12 percent had mild intellectual impairment.
  • 36 percent had moderate intellectual impairment.
  • 52 percent had severe or profound intellectual impairment.
12%
12 percent of people had mild intellectual impairment.
36%
36 percent had moderate intellectual impairment.
53%
52 percent had severe or profound intellectual impairment.

Birth defects

About 40 percent of people are born with heart defects, including a hole in the heart, also called atrial septal defect, and leakage of blood between two heart chambers, also called mitral valve prolapse.

Other common developmental issues:

  • Abnormal facial features (97 percent).
  • Hand and foot defects (62 percent).
  • Musculoskeletal features (55 percent).
  • Shorter than average height (23 percent).
  • Urinary tract defects (13 percent).

Brain

Some have changes in the structure of the brain, as shown by an MRI scan, which gives a picture of the brain. Scientists don’t yet know how these changes affect people. A small number of people have seizures.

  • 16 percent of people have seizures.

Growth

Some children have growth delays and may be shorter than their peers. About one-half have increased weight around the midsection.

Eyes and hearing

Many of those who have ADNP-related syndrome have vision problems, typically farsightedness or crossed eyes. Some people have hearing loss.

  • 74 percent have vision problems.
  • 32 percent of people have hearing loss.
74%
Have vision problems.
32%
Have hearing loss.

Muscle tone

Three-quarters of people have low muscle tone, also called hypotonia. This can lead to delays in sitting and walking.

Sitting and walking

Children often sit and walk late. According to one study of 11 children, children first sat without help between 7.5 months and 12 months of age and started walking between 19 months and 4.5 years of age.

Immune system

Almost two-thirds have repeated infections, including colds and urinary tract infections.

  • 7 out of 11 people have repeated infections.

Feeding and digestion issues

Eating difficulties are common. People may also have vomiting, constipation, and heartburn, or reflux. Some people have difficulty eating.

  • 83 percent have eating difficulties are common.
  • 67 percent have difficulty eating.

Where can I find support and resources?

ADNP Kids Research Foundation

In 2016, the ADNP Kids Research Foundation was founded.  It is a grassroots IRS accredited 501(c)3 based out of Brush Prairie, Washington. 

The ADNP Kids Research Foundation is the only non-profit organization in the world to fund clinical research, publish papers, and promote awareness for ADNP Syndrome.  Itss mission is to advance the awareness and understanding of ADNP Syndrome by supporting research for therapeutic treatments and drug development, increasing awareness and scientific understanding, promoting individualized specialty care and protocol, supporting families and providing information to help all individuals with ADNP realize their full potential and have a better quality of life. 

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.”

Sources and References

The content in this guide comes from published studies about ADNP-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • O’Roak BJ. et al. Science, 338, 1619-1622, (2012). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders www.ncbi.nlm.nih.gov/pubmed/23160955
  • O’Roak BJ. et al. Nature, 485, 246-250, (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations www.ncbi.nlm.nih.gov/pubmed/22495309
  • Helsmoortel C. et al. Nature Genetics, 46, 380-384, (2014). A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
    www.ncbi.nlm.nih.gov/pubmed/24531329
  • Pescosolido MF. et al. Journal of Medical Genetics, 51, 587-589, (2014). Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein ncbi.nlm.nih.gov/pubmed/25057125
  • Vandeweyer G. et al. American Journal of Medical Genetics, Part C Seminars in Medical Genetics, 166C, 315-326, (2014). The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism www.ncbi.nlm.nih.gov/pubmed/25169753
  • Deciphering Developmental Disorders Study Group. Nature, 519, 223-228, (2015). Large-scale discovery of novel genetic causes of developmental disorders,www.ncbi.nlm.nih.gov/pubmed/25533962
  • Gozes I. et al. Journal of Molecular Neuroscience, 56, 751-757, (2015). The compassionate side of neuroscience: Tony Sermone’s undiagnosed genetic journey—ADNP mutation www.ncbi.nlm.nih.gov/pubmed/26168855
  • Van Dijck A. et al. GeneReviews, (2016). ADNP-related intellectual disability and autism spectrum disorder
    www.ncbi.nlm.nih.gov/books/NBK355518
  • Gozes I. et al. Translational Psychiatry, 7, e1043, (2017). Premature primary tooth eruption in cognitive/ motor-delayed ADNP-mutated children
    www.ncbi.nlm.nih.gov/pubmed/28221363
  • Van Dijck A. et al. Biological Psychiatry, 85, 287-297, (2019). Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP www.ncbi.nlm.nih.gov/pubmed/29724491

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