GENE GUIDE

AHDC1-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 AHDC1-Related Syndrome.
a doctor sees a patient

AHDC1-related syndrome is also called Xia-Gibbs syndrome. For this webpage, we will be using the name AHDC1-related syndrome to encompass the wide range of variants observed in the people identified.

AHDC1-related syndrome happens when there are changes in the AHDC1 gene. These changes can keep the gene from working as it should.

Key Role

The AHDC1 gene plays a key role in the growth of the brain.

Symptoms

Because the AHDC1 gene is important for brain activity, many people who have AHDC1-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Speech delay
  • Motor delay
  • Difficulty walking
  • Sleep apnea, a disorder in which breathing stops and starts
  • Seizures
  • Hearing difficulty
  • Brain changes seen on magnetic resonance imaging (MRI)
  • Movement issues, such as ataxia
  • Vision issues
  • Behavioral issues, such as autism
  • Curvature of the spine, also called scoliosis
  • Softening of the voice box that may result from noisy breathing

AHDC1-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 AHDC1 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 AHDC1 plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that AHDC1-related syndrome is often the result of a de novo variant in AHDC1. Many parents who have had their genes tested do not have the AHDC1 genetic variant found in their child who has the syndrome. In some cases, AHDC1-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

AHDC1-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in AHDC1 they will likely have symptoms of AHDC1-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 or I have a change in the AHDC1 gene?

No parent causes their child’s AHDC1-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 AHDC1-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 AHDC1-related syndrome, the sibling’s risk of having a child who has AHDC1-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing AHDC1-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit AHDC1-related syndrome.

As of 2024, about 270 people with AHDC1-related syndrome have been identified in a medical clinic. The first case of AHDC1-related syndrome was described in 2014. Scientists expect to find more people who have the syndrome as access to genetic testing improves.

People who have AHDC1-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Broad forehead
  • Widely spaced eyes
  • Flat bridge of nose
  • Thin upper lip
  • Low-set ears

Scientists and doctors have only just begun to study AHDC1-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 AHDC1-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.

Some researchers have suggested that a frameshift or nonsense variant towards the beginning of the AHDC1 gene may be linked to a higher risk of developing seizures and scoliosis. These medical issues may be less likely with a frameshift or nonsense variant towards the end of the AHDC1 gene. More research is needed to better understand any genetic links to medical features.

Speech and Learning

People with AHDC1-related syndrome had developmental and speech issues. Most people had moderate to severe intellectual disability, and they were non-verbal or had limited speech.

  • 31 out of 37 people had developmental delay (84 percent)
  • 48 out of 60 people had speech issues (80 percent)
  • 27 out of 29 people had intellectual disability (93 percent)
84%
31 out of 37 people had developmental delay.
80%
48 out of 60 people had speech issues.
93%
27 out of 29 people had intellectual disability.

Behavior

Behavioral disorders occurred in people with AHDC1-related syndrome, including autistic behavior, impulsiveness, aggression, self-injury, anxiety, poor social interaction, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD).

  • 17 out of 26 people had a behavioral disorder (65 percent)
  • 21 out of 57 people had autism (37 percent)

Brain

About one-half of people with AHDC1-related syndrome had seizures, with an average age of onset around 4 years old. People had brain changes observed on magnetic resonance imaging (MRI), including developmental defects of the corpus callosum, abnormal white matter (delayed myelination or under myelination), and cerebral atrophy.

  • 27 out of 52 people had seizures (52 percent)
  • 17 out of 34 people had developmental defects of the corpus callosum (50 percent)
  • 9 out of 25 people had abnormal white matter (36 percent)
  • 6 out of 29 people had cerebral atrophy (21 percent)
Human head showing brain outline
52%
27 out of 52 people had seizures.
50%
17 out of 34 people had developmental defects of the corpus callosum.
36%
9 out of 25 people had abnormal white matter.
21%
6 out of 29 people had cerebral atrophy.

Movement

The average age of walking was around 2.5 years old, but some children learned as early as 1.5 years old, and some children were around 6 years old. Most people had hypotonia (low muscle tone). About 7 out of 11 people had ataxia in childhood or adolescence. Some had tremors or bradykinesia (slowness of movement).

  • 52 out of 64 people had hypotonia (81 percent)

Other medical issues

About one-half of people had sleep issues and a growth abnormality. A common sleep issue was sleep apnea, which might have been related to the breathing issues people had, the softening of the voice box, or a collapse of the airway when breathing. Some people developed a curvature of the spine, also called scoliosis, between the ages of 10 to 21 years old.

  • 27 out of 60 people had sleep issues (45 percent)
  • 23 out of 40 people had a growth abnormality (58 percent)
  • 14 out of 35 people had scoliosis (40 percent)
45%
27 out of 60 people had sleep issues.
58%
23 out of 40 people had a growth abnormality.
40%
14 out of 35 people had scoliosis.

Some people had short height and poor feeding after birth. More than one-half of people with AHDC1-related syndrome had strabismus (crossed eyes). Other vision issues included nystagmus (eyes that move rapidly without control) and myopia (nearsightedness).

  • 30 out of 53 people had strabismus (57 percent)

Where can I find support and resources?

Xia-Gibbs Society

Xia-Gibbs Society is a not-for-profit corporation formed in the USA for charitable purposes. Our mission is to support and advocate for those with Xia-Gibbs Syndrome (XGS) and their families, to raise awareness and to assist with scientific and medical research.

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 AHDC1-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Yang H. et al. Cold Spring Harbor Molecular Case Studies, 1, a000562, (2015). De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay www.ncbi.nlm.nih.gov/pubmed/27148574
  • Jiang Y. et al. American Journal of Medical Genetics Part A, 176, 1315-1326, (2018). The phenotypic spectrum of Xia-Gibbs syndrome www.ncbi.nlm.nih.gov/pubmed/29696776
  • Genetics Home Reference, AHDC1 gene ghr.nlm.nih.gov/gene/AHDC1
  • Baga, M., Ivanovski, I., Contrò, G., Caraffi, S. G., Spagnoli, C., Cesaroni, C. A., Neri, A., Peluso, F., Pollazzon, M., … & Fusco, C. (2024). Novel insights from clinical practice: Xia-Gibbs syndrome with pes cavus, conjunctival melanosis, and eye asymmetry due to a de novo AHDC1 gene variant – A case report and a brief review of the literature. Molecular Syndromology, 15(1), 63-70. https://pubmed.ncbi.nlm.nih.gov/38357260/
  • Chander, V., Wangler, M., Gibbs, R., & Murdock, D. Xia-Gibbs syndrome. 2021 Dec 9. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK575793/

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