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GENE GUIDE

RELN-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 in 2025. 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 RELN-Related Syndrome.
a doctor sees a patient

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

Key Role

The RELN gene plays an important role in brain development, memory processing, and cognition.

Symptoms

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

  • Developmental delay
  • Intellectual disability
  • Epilepsy
  • Autism
  • Brain changes seen on magnetic resonance imaging (MRI)
  • Difficulty expressing and understanding written and spoken language

Autosomal dominant conditions

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

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

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

RELN-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 RELN gene: one copy from their mother’s egg, and one copy from their father’s sperm. 

Some people have variants to their genes that prevent them from working properly. A variant in one copy of the GENE gene has little or no effect on their health — because one working copy is enough. People who have one working copy of the gene and one non-working copy of the gene are called ‘carriers’. Some people have genes where both copies do not work as they should. In these cases, the person has inherited non-working copies of the gene from both parents. This can lead to physical issues, developmental issues, or both.

RELN-related syndrome is an autosomal recessive genetic condition. To be affected with symptoms of an autosomal recessive genetic condition, a person has two damaging variants on both copies of their RELN. For someone with an autosomal recessive genetic syndrome, every time they have a child they will pass on one non-working copy of RELN.

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

Autosomal Recessive Genetic Syndrome

GENE / gene
Carrier
father
GENE / gene
Carrier
mother
gene / gene
Non-carrier child
GENE / gene
Carrier of the variant
GENE / gene
Carrier of the variant
GENE / GENE
Child with autosomal recessive condition

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

No parent causes their child’s RELN-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 foreseen or stopped.

Autosomal dominant conditions

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

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

Autosomal recessive conditions

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 the same biological parents to a child with an autosomal recessive genetic condition, having another child who has RELN-related syndrome is almost always 25 percent.
  • The chance of two carrier parents having a child who is also a carrier is 50 percent. Carriers are not expected to have symptoms. 
  • The chance of them having a child who is not a carrier at all is 25 percent.

For a person who has RELN-related syndrome, the risk of having a child who has the same syndrome depends on their partner. 

  • If their partner is a carrier, they have a 50 percent chance of having a child who has the syndrome and a 50 percent chance of having a child who is a carrier. 

If their partner is not a carrier, they have nearly a 0 percent chance of having a child who has the syndrome and a 100 percent chance of having a child who is a carrier.

As of 2025, at least 98 people with RELN-related syndrome have been identified in a medical clinic.

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

  • Smaller than average head size
  • Low sloping forehead

Scientists and doctors have only just begun to study RELN-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 RELN-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/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.

Researchers are now finding that genetic variants in the RELN gene that are associated with neurodevelopment can be caused by one RELN genetic variant or two RELN genetic variants. Below, we have summarized the medical features identified for these two neurodevelopmental conditions.

Learning

People with RELN-related syndrome may have developmental delay or intellectual disability. In the medical research, many people with an RELN genetic variant do not have any described cognitive challenges.

Behavior

People with RELN-related syndrome might have behavioral issues such as autism. Several large-scale research studies investigating autistic people have identified people with RELN genetic variants. In these studies, the researchers usually do not have many medical details on the participants.

Brain

A subgroup of people with a RELN genetic variant had a condition called autosomal dominant epilepsy with auditory features (ADEAF). An ADEAF diagnosis is based on having certain clinical medical issues, and a RELN genetic variant does not automatically result in an ADEAF diagnosis.

People with ADEAF and a RELN genetic variant had focal sensory auditory seizures and/or focal cognitive seizures with challenges in understanding written and spoken language. They also had normal brain imaging seen on magnetic resonance imaging (MRI). Age of seizure onset ranged from 1 to 50 years old.

Other people with an RELN genetic variant had neurological medical issues, including seizures or brain changes seen on MRI. In one family, 6 people with a specific RELN variant (p.Thr3192Ser) had symptoms associated with schizophrenia.

  • 21 out of 34 people had seizures (62 percent)
  • 6 people had brain changes seen on MRI
  • 6 people had symptoms associated with schizophrenia

Other medical findings

Seven people in one family had an inflammatory condition of the spine called ankylosing spondylitis. Each person had a specific RELN variant (p.Ser2486Gly). People with other RELN genetic variants have not been reported to have ankylosing spondylitis.

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.”

Sources and References

  • Balza, C., Garofalo, G., Cos, T., Désir, J., Kang, X., Keymolen, K., Soblet, J., Van Berkel, K., Vilain, C., … & Cassart, M. (2021). A prenatal case of lissencephaly with cerebellar hypoplasia: New mutation in RELN gene. Clinical Case Reports, 9(12), e04882. doi:10.1002/ccr3.4882
  • Chen, Y., Zhu, Y., Zhong, W., He, J., Gou, H., & Zhu, Y. (2024). Identification of autosomal dominant lateral temporal epilepsy caused by a novel mutation in RELN in China: A case report. Acta Epileptologica, 6(1), 31. doi:10.1186/s42494-024-00179-y
  • Fang, X. Q., Zhang, R. R., & Liu, X. W. (2022). Heterozygous missense mutation of the RELN gene is one of the causes of epilepsy. Neurological Research, 44(3), 262-267. doi:10.1080/01616412.2021.1979748
  • Li, Z., Wang, F., He, Z., Guo, Q., Zhang, J., & Liu, S. (2024). RELN gene-related drug-resistant epilepsy with periventricular nodular heterotopia treated with radiofrequency thermocoagulation: A case report. Frontiers in Neurology, 15, 1366776. doi:10.3389/fneur.2024.1366776
  • Garshasbi, M., Mahmoudi, M., Razmara, E., Vojdanian, M., Aslani, S., Farhadi, E., Jensen, L. R., Arzaghi, S. M., Poursani, S., … & Jamshidi, A. (2020). Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. European Journal of Human Genetics, 28(6), 754-762. doi:10.1038/s41431-020-0573-4
  • Riva, M., Ferreira, S., Hayashi, K., Saillour, Y., Medvedeva, V. P., Honda, T., Hayashi, K., Altersitz, C., Albadri, S., … & Pierani, A. (2024). De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism. The Journal of Clinical Investigation, 134(16), e153097. doi:10.1172/jci153097
  • Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., … & Eichler, E. E. (2020). Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nature Communications, 11(1), 4932. doi:10.1038/s41467-020-18723-y
  • Zhou, Z., Hu, Z., Zhang, L., Hu, Z., Liu, H., Liu, Z., Du, J., Zhao, J., Zhou, L., … & Shen, L. (2016). Identification of RELN variation p.Thr3192Ser in a Chinese family with schizophrenia. Scientific Reports, 6, 24327. doi:10.1038/srep24327

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