Autism spectrum disorder (ASD) is a neurological and developmental disorder that begins early in childhood and lasts throughout a person's life. It affects how a person acts and interacts with others, communicates, and learns. It includes what used to be known as Asperger syndrome and pervasive developmental disorders.

It is called a "spectrum" disorder because people with ASD can have a range of symptoms. People with ASD might have problems talking with you, or they might not look you in the eye when you talk to them. They may also have restricted interests and repetitive behaviors. They may spend a lot of time putting things in order, or they may say the same sentence again and again. They may often seem to be in their "own world."

At well-child checkups, the health care provider should check your child's development. If there are signs of ASD, your child will have a comprehensive evaluation. It may include a team of specialists, doing various tests and evaluations to make a diagnosis.

The causes of ASD are not known. Research suggests that both genes and environment play important roles.

There is currently no one standard treatment for ASD. There are many ways to increase your child's ability to grow and learn new skills. Starting them early can lead to better results. Treatments include behavior and communication therapies, skills training, and medicines to control symptoms.

Autism spectrum disorder (ASD) is a condition that appears very early in childhood development, varies in severity, and is characterized by impaired social skills, communication problems, and repetitive actions. These difficulties can interfere with affected individuals' ability to function in social, academic, and employment settings. People with ASD also have an increased risk of psychiatric problems such as anxiety, depression, obsessive-compulsive disorder, and eating disorders.

From as early as 1 to 2 years of age, people with ASD have an impaired ability to interact with other people; they are often more comfortable dealing with objects. Affected individuals have difficulty understanding and using non-verbal social cues such as eye contact, facial expressions, gestures, and body language. Inability to recognize and use these cues makes it hard for affected individuals to understand the feelings of others or communicate their own feelings appropriately. Signs of ASD, such as reduced eye contact and social interaction, can sometimes be detected before age 2. However, the condition is usually diagnosed between ages 2 and 4, when more advanced communication and social skills, such as learning to play with others, typically begin to develop.

Repetitive actions in ASD can include simple actions such as rocking, hand-flapping, or repetition of words or noises (echolalia). Affected individuals often dwell on or repeatedly express particular thoughts; this trait is called perseveration. People with ASD tend to be rigid about their established routines and may strongly resist disruptions such as changes in schedule. They may also have difficulty tolerating sensory stimuli such as loud noises or bright lights.

While social and communication difficulties and unusual actions define ASD, affected individuals can have a wide range of intellectual abilities and language skills. A majority of people with ASD have mild to moderate intellectual disability, while others have average to above-average intelligence. Some have particular cognitive abilities that greatly surpass their overall level of functioning, often in areas such as music, mathematics, or memory.

Some people with ASD do not speak at all, while others use language fluently. However, fluent speakers with ASD often have problems associated with verbal communication. They might speak in a monotone voice, have unusual vocal mannerisms, or choose unusual topics of conversation.

Several diagnoses that used to be classified as separate conditions are now grouped together under the diagnosis of ASD. For example, autistic disorder was a term that was used when affected individuals had limited or absent verbal communication, often in combination with intellectual disability. By contrast, Asperger syndrome was a diagnosis formerly applied to affected individuals of average or above-average intelligence who were not delayed in their language development. The broader diagnosis of ASD was established because many affected individuals fall outside of the strict definitions of the narrower diagnoses, and their intellectual and communication abilities may change over time. However, some individuals who were previously diagnosed with one of the subtypes now do not meet all the criteria of the new umbrella diagnosis.

ASD is a common condition, and the number of children diagnosed with ASD has been increasing rapidly in the past few decades. In 2021, the prevalence of the disorder in the United States is estimated at 1 in 44 children. In the 1980s, before the term ASD was used, the prevalence of autism was reported to be about 1 in 2,000. However, it is unclear whether this represents a true increase in the prevalence of ASD or reflects changes in the way characteristics of the disorder have been diagnosed and categorized.

ASD is more than four times as common in boys than it is in girls.

Autism represents a broad group of developmental disorders characterized by impaired social interactions, problems with verbal and nonverbal communication, and repetitive behaviors or severely limited activities and interests.

What is autism?

Autism - or more precisely the autism spectrum disorders (ASDs) - represent a broad group of developmental disorders characterized by impaired social interactions, problems with verbal and nonverbal communication, and repetitive behaviors or severely limited activities and interests.

The ASDs include a variety of medical autism diagnoses, which vary in the severity of the individual symptoms and include autistic disorder (sometimes called classical autism), Asperger's syndrome and a general diagnostic category called Pervasive Developmental Disorders (PDD).

Autism has become the most commonly diagnosed childhood developmental disorder. According to the Centers for Disease Control Prevention in 2007, autism spectrum disorders now affect 1 in every 150 children in the United States. Statistics from the U.S. Department of Education and other government agencies indicate that autism diagnoses are increasing at the rate of 10 to 17 percent per year.

Autism can affect any individual and is not based on ethnic, racial or social background. The incidence of autism is the same all around the world. It is four times more common in boys than in girls.

What are the symptoms of autism?

Autism usually develops before 3 years of age and affects each individual differently and to varying degrees. It ranges in severity from relatively mild social and communicative impairments to a severe disability requiring lifelong parental, school and societal support.

The hallmark symptom of autism is impaired social interaction. Children with autism may fail to respond to their name and often avoid eye contact with other people. They have difficulty interpreting what others are thinking or feeling because they don't understand social cues provided by tone of voice or facial expressions and they don't watch other people's faces to pick up on these cues.

Many children with autism engage in repetitive movements such as rocking, spinning, twirling or jumping, or in self-abusive behavior such as hand biting or head-banging.

Of children being diagnosed now with an autism spectrum disorder, about half will have intellectual disabilities defined by nonverbal IQ testing, and 25 percent will also develop seizures. Though most children show signs of autism in the first year of life, about 30 percent will seem fine and then regress in both their language and social interactions at around 18 months of age.

About 30 percent of children with autism have physical signs of some alteration in early development such as physical features that differ from their parents (sometimes called dysmorphic features), small head size (microcephaly) or structural brain malformations.

How is autism diagnosed?

Diagnosis of autism is based on standardized testing plus a clinical evaluation by an autism specialist. These professionals are usually psychologists, psychiatrists, developmental pediatricians, pediatric neurologists or medical geneticists.

The diagnosis of autism is made when there are a specific number of symptoms as defined by the Diagnostic and Standard Manual of Mental Disorders (DSM-5, published in 2013). Some commonly used diagnostic tests are the CARS (Childhood Autism Rating Scale), the ABC (Autism Behavior Checklist) and the GARS (Gilliam Autism Rating Scale). Formal diagnosis by an autism specialist usually depends on completing the ADOS (Autism Diagnostic Observation Scale), and ADI-R (Autism Diagnostic Interview-Revised). The CHAT (Checklist for Autism in Toddlers) is often used in pediatrician's offices to screen for autism symptoms.

When physical features, small head size or brain malformations are present or there is a family history of relatives with autism, genetic testing such as chromosome analysis and single-gene testing is done.

What is the treatment for autism?

There is currently no cure for autism. However, autism can be managed and shaped at a young age, even as early as pre-school. Early intensive therapy can have a positive effect on development later in life.

Treatment of autism involves medical and behavioral therapies to help children with conversational language and social interactions. Treatment also involves helping children decrease their repetitive, self-stimulatory behaviors, tantrums and self-injurious behavior.

Medications can help treat specific symptoms such as aggressive or self-injurious behavior, inattention, poor sleep and repetitive behaviors. However, no medications are autism specific and medications should be used in conjunction with a family-centered, behavioral and educational program.

Is autism inherited?

Scientists are not certain what causes autism, but it's likely that both genetics and environment play a role.

The causes of autism may be divided into 'idiopathic', (of unknown cause) which is the majority of cases, and 'secondary,' in which a chromosome abnormality, single-gene disorder or environmental agent can be identified. Approximately 15 percent of individuals with autism can be diagnosed with secondary autism; the remaining 85 percent have idiopathic autism.

Exposure during pregnancy to rubella (German measles), valproic acid, and thalidomide, are recognized causes of secondary autism; however, it remains unclear whether those who develop autism after such an exposure are also genetically predisposed.

The search for new environmental causes of secondary autism has centered primarily on childhood immunizations given around the time that regressive-onset autism is recognized. Both childhood immunizations and mercury in thimerosal, which was used as a preservative in some routine immunizations until 2001, have both been under scrutiny; however, no scientific evidence for a relationship between vaccines and autism has been identified.

Researchers have identified a number of genes associated with autism. Studies of people with autism have found irregularities in several regions of the brain. Other studies suggest that people with autism have abnormal levels of serotonin or other neurotransmitters in the brain. These abnormalities indicate that autism usually results from the disruption of normal brain development early in fetal development caused by defects in genes that control brain growth and that regulate how neurons communicate with each other. These are preliminary findings and require further study.

The risk that a brother or sister of an individual who has idiopathic autism will also develop autism is around 4 percent, plus an additional 4 to 6 percent risk for a milder condition that includes language, social or behavioral symptoms. Brothers have a higher risk (about 7 percent) of developing autism, plus the additional 7 percent risk of milder autism spectrum symptoms, over sisters whose risk is only about 1 to 2 percent.

When the cause of autism is a chromosome abnormality or a single-gene alteration, the risk that other brothers and sisters will also have autism depends on the specific genetic cause.

Scientists don't know exactly what causes autism spectrum disorder (ASD).

Autism was first described in the 1940s, but very little was known about it until the last few decades. Even today, there is a great deal that we don't know about autism.

Because the disorder is so complex and no two people with autism are exactly alike, there are probably many causes for autism. It is also likely that there is not a single cause for autism, but rather that it results from a combination of causes.

Scientists are studying some of the following as possible causes of or contributors to ASD.

Genes and ASD

A great deal of evidence supports the idea that genes are one of the main causes of or a major contributor to ASD. More than 100 genes on different chromosomes may be involved in causing ASD, to different degrees.

Many people with autism have slight changes, called mutations, in many of these genes. However, the link between genetic mutations and autism is complex:

• Most people with autism have different mutations and combinations of mutations. Not everyone with autism has changes in every gene that scientists have linked to ASD.
• Many people without autism or autism symptoms also have some of these genetic mutations that scientists have linked to autism.

This evidence means that different genetic mutations probably play different roles in ASD. For example, certain mutations or combinations of mutations might:

• Cause specific symptoms of ASD
• Control how mild or severe those symptoms are
• Increase susceptibility to autism. This means someone with one of these gene mutations is at greater risk for autism than someone without the mutation.

Genes: Bits of DNA that carry instructions for "building" your body.

Chromosomes: Packages of DNA and genes in the cells of the body.

Interactions Between Genes and the Environment

If someone is susceptible to ASD because of genetic mutations, then certain situations might cause autism in that person.

For instance, an infection or contact with chemicals in the environment could cause autism in someone who is susceptible because of genetic mutations. However, someone who is genetically susceptible might not get an ASD even if he or she has the same experiences.

Other Biological Causes

Researchers are also looking into biological factors other than genes that might be involved in ASD. Some of these include:

• Problems with brain connections
• Problems with growth or overgrowth in certain areas of the brain
• Problems with metabolism (the body's energy production system)
• Problems in the body's immune system, which protects against infections

Currently, there is no scientific evidence that vaccines or any material used to make or preserve vaccines causes or contributes to ASD. A great deal of research projects have come to the same conclusion, including those conducted independently and recently.

The Centers for Disease Control and Prevention (CDC), another agency within the U.S. Department of Health and Human Services, conducts and supports most of the federal studies on vaccines and autism. The CDC also provides the most accurate and up-to-date information about research on ASD and vaccines, including studies supported by the federal government and those funded independently.

Autism, also known as autism spectrum disorder, is a broad range of conditions that affect communication and behavior, usually appearing by age 2. The Centers for Disease Control and Prevention (CDC) reports that autism affects 1 in 36 children. This data reflects increased ability to recognize and diagnose characteristics of autism spectrum disorder earlier in a child's life.

People with autism may have difficulty with communication and social interaction; restricted interests and repetitive behaviors; and inability to function effectively in school, work, and other areas of life. Although scientists are still trying to understand why some people develop autism and others don’t, risk factors may include:

• A sibling with autism
• Older parents
• Certain genetic conditions, such as Down, fragile X, and Rett syndromes
• Very low birth weight

What Causes Autism?

Studies indicate the rate of autism is rising, but causes are not well-understood. Scientists have found rare gene changes, or mutations, as well as small common genetic variations in people with autism, implying a genetic component. A growing area of research focuses on interaction of genetic and environmental factors. For example, a woman’s exposure to harmful contaminants during pregnancy may trigger a genetic mutation leading to autism in her child. No link has been found between autism and vaccines, including those containing thimerosal, a mercury-based compound.

What Environmental Factors May Be Associated With Autism?

Progress has been made toward understanding different environmental risk factors, and the clearest evidence involves events before and during birth, such as:

• Advanced parental age at time of conception
• Prenatal exposure to air pollution or certain pesticides
• Maternal obesity, diabetes, or immune system disorders
• Extreme prematurity or very low birth weight
• Any birth difficulty leading to periods of oxygen deprivation to the baby’s brain

But these factors alone are unlikely to cause autism. Rather, they appear to increase a child’s risk for developing autism when combined with genetic factors.

What Is NIEHS Doing?

NIEHS-funded researchers are primarily interested in risk factors related to gene and environment interaction. Key findings are grouped by topic below.

Air pollution – Researchers found early-life exposure to air pollution may be a risk factor for autism.

• Children of mothers living near a freeway, and traffic-related pollution, during the third trimester of pregnancy were twice as likely to develop ASD. A distance of 1,014 feet, or a little less than 3.5 football fields, was considered near a freeway.
• Children with a mutation in a gene called MET, combined with high levels of exposure to air pollution, may have increased risk.

Prenatal conditions and maternal factors – Problems with a mother’s immune system, certain metabolic conditions, or inflammation during pregnancy may be linked with higher autism risk for her children.

• Some mothers of autistic children have antibodies, or proteins in the body that fight infection, that may interfere with their children’s brain development, possibly leading to autism.
• Maternal diabetes or obesity are linked to increased likelihood of having a child with autism or other developmental disability.
• Fever during pregnancy was associated with increased risk of autism for children.

Metals, pesticides, and other contaminants – Prenatal and early childhood exposure to heavy metals, like mercury, lead, or arsenic; altered levels of essential metals like zinc or manganese; pesticides; and other contaminants cause concern.

• For people in the Republic of Seychelles, fish consumption is high and a primary way they are exposed to mercury. But a study there found no association between this type of prenatal, dietary mercury exposure and autism.
• Researchers found that after adjusting for dietary and other mercury sources, children with autism had similar mercury levels in blood as those without.
• A study of twins used baby teeth to determine and compare levels of lead, manganese, and zinc in children with autism to their twin without the condition. Autistic children were low on manganese and zinc, metals essential to life, but had higher levels of lead, a harmful metal during specific developmental time periods studied.
• Researchers further found that altered zinc-copper cycles, which regulate metal metabolism in the body, are disrupted in ASD cases.
• Maternal exposure to insecticides during early pregnancy was associated with higher risk of autism in their children.
• Researchers are also studying contaminants such as Bisphenol A, phthalates, flame retardants, and polychlorinated biphenyls to see if they affect early brain development and possibly play a role in autism.

Nutrition – NIEHS-funded studies have found taking prenatal vitamins may help lower autism risk. Furthermore, research suggests taking vitamins and supplements might provide protective effects for those exposed to certain environmental contaminants during pregnancy.

• Women were less likely to have a child with autism if they took a daily prenatal vitamin during the three months before and first month of pregnancy, compared to women not taking vitamins. This finding was more evident in women and children with genetic variants that made them more susceptible to developing autism.
• Folic acid is a source of the protective effects of prenatal vitamins. Women who took the daily recommended dosage during the first month of pregnancy had a reduced risk of having a child with autism.
• Pregnant mothers who used multivitamins, with or without additional iron or folic acid, were less likely to have a child with autism and intellectual disability.
• Folic acid intake during early pregnancy may reduce the risk of having a child with autism for those women with high exposure to air pollution , and pesticides.
• Maternal prenatal vitamin intake during the first month of pregnancy may also reduce ASD recurrence in siblings of children with ASD in high-risk families.

Notable NIEHS-funded, large-scale studies – NIEHS-funded scientists are working to better understand the environmental contributors to ASD through their continued work on the Childhood Autism Risk from Genetics and the Environment (CHARGE) study, the Markers of Autism Risk in Babies - Learning Early Signs (MARBLES) study, and The Early Autism Risk Longitudinal Investigation (EARLI) study.  

CHARGE, with more than 1,800 children enrolled, seeks to clarify the roles of genetics and environmental exposures in autism. Results indicate a variety of exposures may be associated with increased risk, including pesticides, air pollution, and maternal metabolic or immune conditions

MARBLES, with more than 400 mother-child pairs, is a unique study in that it obtains information about how exposures before, during, and after pregnancy may contribute to autism. Recent research explores the effect that prenatal exposure to phthalates and prenatal vitamins may have on autism development.

EARLI is another study that enrolled a large group of pregnant mothers of children with autism. The newborn child – the sibling to the child with ASD – was subsequently followed through three years of age to see if he or she was diagnosed with ASD. The EARLI study continues to follow the children and examine possible environmental risk factors for autism and possible links between genes and the environment, known as gene-environment interactions.

Key Findings: The association between assisted reproductive technology and autism spectrum disorder

Researchers have published new studies looking at the relationship between assisted reproductive technology (ART) and autism spectrum disorder (ASD) among a group of children born in California between 1997 and 2007. The key findings from each study are highlighted below. These findings are important for researchers, healthcare providers, and public health professionals as we strive to better understand what factors put children at risk for ASD.

Does assisted reproductive technology increase the risk for autism spectrum disorder?

• Overall, children conceived using ART were about two times more likely to be diagnosed with ASD compared to children conceived without using ART.
• Evidence suggests that for pregnancies conceived with ART, the increased risk for ASD is, in large part, due to the higher likelihood of adverse pregnancy and delivery outcomes. In other words, using ART may lead to factors that are known to put children at risk for ASD, such as being born a twin or multiple (triplets, quadruplets, etc.), being born too early, or being born too small.
• More research is needed to explore what exactly underlies the observed relationship between ART and ASD.
• However, these findings suggest that single embryo transfer, where appropriate, may reduce the risk of ASD among children conceived using ART.

Does type of ART procedure impact the relationship between assisted reproductive technology and autism spectrum disorder?

• Among children conceived using ART, about 0.8% of those born as singletons (only one baby carried during the pregnancy) and about 1.2% of those born as a twin or multiple were diagnosed with ASD.
• Children conceived using ART were more likely to be diagnosed with ASD if intracytoplasmic sperm injection (ICSI) was used compared to conventional in vitro fertilization. ICSI and in vitro fertilization are procedures in which fertilization (a sperm entering an egg) occurs outside of the body; ICSI occurs by injecting a sperm directly into an egg while in vitro fertilization involves mixing sperm with eggs in a laboratory dish and allowing fertilization to occur.
• More research is needed to explore what exactly underlies the observed relationship between ICSI and ASD.

Does autism diagnosis age or symptom severity differ among children according to whether ART was used to achieve pregnancy?

• Among children receiving services for autism, children who had been conceived using ART had a lower median age of autism diagnosis (3.3 years) than those who were not conceived using ART (4.0 years).
• Despite being identified earlier, the children who had been conceived using ART were less likely to have co-occurring intellectual disability or to be classified as having the most severe deficits in communication and social functioning than children who were not conceived using ART.
• The differences in autism diagnosis age were largely accounted for by socio-demographic differences between ART-conceived and non-ART-conceived children, and the differences in autism symptom severity were entirely accounted for by socio-demographic differences between the groups.
• These findings indicate that earlier identification of autism in children who come from more advantaged families and exhibit less severe autism symptoms contributes to the ART-autism association observed in the overall population. This is likely due to more advantaged families having greater access to ART services.

More About These Studies

These studies used one of the largest population-based datasets on ART. Specifically, these studies examined data obtained from three sources: the California Birth Master Files, the California Department of Developmental Services autism caseload records, and CDC’s National ART Surveillance System. These datasets included a total of almost 6 million births, including almost 50,000 children conceived through ART. A key advantage of this study is its large size, which provides more confidence in the results than previous studies that looked at relationships between ART and ASD.

Q: What are mitochondrial diseases or disorders?

A: Mitochondria are tiny parts of almost every cell in your body. Mitochondria are like the power house of the cells. They turn sugar and oxygen into energy that the cells need to work.

In mitochondrial diseases, the mitochondria cannot efficiently turn sugar and oxygen into energy, so the cells do not work correctly.

There are many types of mitochondrial disease, and they can affect different parts of the body: the brain, kidneys, muscles, heart, eyes, ears, and others. Mitochondrial diseases can affect one part of the body or can affect many parts. They can affect those part(s) mildly or very seriously.

Not everyone with a mitochondrial disease will show symptoms. However, when discussing the group of mitochondrial diseases that tend to affect children, symptoms usually appear in the toddler and preschool years.

Mitochondrial diseases and disorders are the same thing.

Q: Is there a relationship between mitochondrial disease and autism?

A: A child with a mitochondrial disease:

• may also have an autism spectrum disorder,
• may have some of the symptoms/signs of autism, or
• may not have any signs or symptoms related to autism.

A child with autism may or may not have a mitochondrial disease. When a child has both autism and a mitochondrial disease, they sometimes have other problems as well, including epilepsy, problems with muscle tone, and/or movement disorders.

More research is needed to find out how common it is for people to have autism and a mitochondrial disorder. Right now, it seems rare. In general, more research about mitochondrial disease and autism is needed.

Q: What is regressive encephalopathy?

A: Encephalopathy is a medical term for a disease or disorder of the brain. It usually means a slowing down of brain function.

Regression happens when a person loses skills that they used to have like walking or talking or even being social.

Regressive encephalopathy means there is a disease or disorder in the brain that makes a person lose skills they once had.

We know that sometimes children with mitochondrial diseases seem to be developing as they should, but around toddler or preschool age, they regress. The disease was there all the time, but something happens that “sets it off”. This could be something like malnutrition, an illness such as flu, a high fever, dehydration, or it could be something else.

Q: Is there a relationship between autism and encephalopathy?

A: Most children with an autism spectrum disorder do not and have not had an encephalopathy. Some children with an autism spectrum disorder have had regression and some have had a regressive encephalopathy.

Q: What do we know about the relationship between mitochondrial disease and other disorders related to the brain?

A: Different parts of the brain have different functions. The area of the brain that is damaged by a mitochondrial disease determines how the person is impacted. This means that a person could have seizures; trouble talking or interacting with people; difficulty eating; muscle weakness, or other problems. They could have one issue or several.

Q: Do vaccines cause or worsen mitochondrial diseases?

A: As of now, there are no scientific studies that say vaccines cause or worsen mitochondrial diseases. We do know that certain illnesses that can be prevented by vaccines, such as the flu, can trigger the regression that is related to a mitochondrial disease. More research is needed to determine if there are rare cases where underlying mitochondrial disorders are triggered by anything related to vaccines. However, we know that for most children, vaccines are a safe and important way to prevent them from getting life-threatening diseases.

Q: Are all children routinely tested for mitochondrial diseases? What about children with autism?

A: Children are not routinely tested for mitochondrial diseases. This includes children with autism and other developmental delays.

Testing is not easy and may involve getting multiple samples of blood, and often samples of muscle. Doctors decide whether testing for mitochondrial diseases should be done based on a child’s signs and symptoms.

Q: Should I have my child tested for a mitochondrial disease?

A: If you are worried that your child might have a mitochondrial disease, talk to your child’s doctor.

Normal Function

The ADNP gene provides instructions for making a protein that helps control the activity (expression) of other genes through a process called chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. As part of the remodeling process, the ADNP protein attaches to DNA and interacts with groups of proteins called SWI/SNF complexes, which direct changes in the structure of chromatin.

By regulating gene expression, the ADNP protein is involved in many aspects of development. It is particularly important for regulation of genes involved in normal brain development, and it likely controls the activity of genes that direct the development and function of other body systems.

Health Conditions Related to Genetic Changes

ADNP syndrome

At least 22 ADNP gene mutations have been found to cause ADNP syndrome. This condition features intellectual disability and autism spectrum disorder, which is characterized by impaired communication and social interactions. Affected individuals can also have distinctive facial features and a wide variety of other signs and symptoms. Most ADNP gene mutations are thought to lead to the production of an abnormally short ADNP protein. Although it is unclear how these genetic changes cause ADNP syndrome, researchers speculate that the abnormally short protein can attach to DNA but cannot interact with SWI/SNF complexes. As a result, chromatin remodeling is impaired. Disturbance of this process alters the activity of many genes and disrupts the development or function of several of the body's tissues and organs, including the brain. These changes likely explain the intellectual disability, autism spectrum disorder, and other diverse signs and symptoms of ADNP syndrome.

Autism spectrum disorder

MedlinePlus Genetics provides information about Autism spectrum disorder

Other Names for This Gene

• activity-dependent neuroprotective protein
• activity-dependent neuroprotector
• activity-dependent neuroprotector homeobox protein
• ADNP homeobox 1
• ADNP1
• HVDAS
• KIAA0784
• MRD28

Genomic Location

Normal Function

The ARID1B gene provides instructions for making a protein that forms one piece (subunit) of several different SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

Through their ability to regulate gene activity, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. The ARID1B protein and other SWI/SNF subunits are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

The ARID1B subunit is able to attach (bind) to DNA and is thought to help target SWI/SNF complexes to the chromatin location that needs to be remodeled.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

More than 150 variants (also known as mutations) in the ARID1B gene have been found to cause Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. Most ARID1B gene variants involved in Coffin-Siris syndrome lead to an abnormally short, nonfunctional protein. As a result, affected individuals have half the normal amount of functional ARID1B protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that ARID1B gene variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, which could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an increased risk of cancer (see below).

Autism spectrum disorder

At least 13 ARID1B gene variants have been identified in people with autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. Some affected individuals also have other features, including intellectual disability, severe speech problems, and brain malformations. The ARID1B gene variants associated with ASD result in a reduced amount of the ARID1B protein or impair the protein's function in chromatin remodeling. These changes likely affect the control of gene expression and interfere with normal brain development, but the specific relationship between the variants and ASD is unknown.

Other disorders

Variants in the ARID1B gene can cause intellectual disability without other hallmark features of Coffin-Siris syndrome (described above). As in Coffin-Siris syndrome, the gene variants that cause intellectual disability lead to an abnormally short, nonfunctional protein, and affected individuals have half the normal amount of ARID1B protein. It is unclear why some people with an ARID1B gene variant develop intellectual disability and others have the additional features of Coffin-Siris syndrome.

Cancers

Variants in the ARID1B gene are involved in several types of cancer, including breast cancer, a childhood cancer of nerve tissue called neuroblastoma, and a type of blood cancer called diffuse large B-cell lymphoma. These variants are somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. The mechanism by which variants in the ARID1B gene contribute to cancer is unknown, although it is thought that changes in SWI/SNF complexes are involved. These changes may impair normal cell differentiation, which leads to the overgrowth of certain cell types, causing cancer. Alternatively, abnormal SWI/SNF complexes may disrupt the regulation of genes that help control the growth and division of cells, which leads to cancer. It is likely that other genetic changes in addition to ARID1B gene variants are necessary for cancer development.

Other Names for This Gene

• 6A3-5
• ARI1B_HUMAN
• ARID domain-containing protein 1B
• AT rich interactive domain 1B (SWI1-like)
• AT-rich interactive domain-containing protein 1B
• BAF250B
• BRG1-associated factor 250b
• BRG1-binding protein ELD/OSA1
• BRIGHT
• DAN15
• ELD (eyelid)/OSA protein
• ELD/OSA1
• KIAA1235
• MRD12
• OSA2
• P250R

Genomic Location

Normal Function

The ASH1L gene, also known as KMT2H, provides instructions for making an enzyme, called lysine-specific methyltransferase 2H, that is found in many organs and tissues of the body. Lysine-specific methyltransferase 2H functions as a histone methyltransferase. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity of certain genes. Lysine-specific methyltransferase 2H appears to turn on (activate) certain genes that are especially important for development of the brain.

Health Conditions Related to Genetic Changes

Autism spectrum disorder

At least seven ASH1L gene mutations have been identified in people with autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. Some ASH1L gene mutations associated with ASD change one building block (amino acid) in the lysine-specific methyltransferase 2H enzyme. Others delete genetic material in the ASH1L gene sequence or result in a premature stop signal that leads to an abnormally short enzyme. As a result of these mutations, the enzyme is nonfunctional. A lack of functional lysine-specific methyltransferase 2H enzyme disrupts histone methylation. The resulting changes in the expression of genes regulated by lysine-specific methyltransferase 2H affect brain development and increase the risk of ASD. Normal variations in other genes, as well as environmental risk factors, such as parental age, birth complications, and others that have not been identified, also affect an individual's risk of developing this complex condition.

Other Names for This Gene

• absent small and homeotic disks protein 1 homolog
• ASH1
• ash1 (absent, small, or homeotic)-like
• ASH1-like protein
• ASH1L1
• histone-lysine N-methyltransferase ASH1L
• huASH1
• KMT2H
• lysine N-methyltransferase 2H
• probable histone-lysine N-methyltransferase ASH1L

Genomic Location

Normal Function

The CHD2 gene provides instructions for making a protein called chromodomain DNA helicase protein 2. This protein is found in cells throughout the body and regulates gene activity (expression) through a process known as chromatin remodeling. Chromatin is the complex of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. When DNA is tightly packed, gene expression is lower than when DNA is loosely packed. Chromodomain DNA helicase protein 2 appears to play an important role in the brain, although its function is not well understood. Research suggests that it may help control development or functioning of nerve cells (neurons).

Health Conditions Related to Genetic Changes

CHD2 myoclonic encephalopathy

At least 30 mutations in the CHD2 gene have been found to cause CHD2 myoclonic encephalopathy, a condition characterized by recurrent seizures (epilepsy), abnormal brain function (encephalopathy), and intellectual disability beginning in childhood. About half of these mutations delete pieces of DNA from the CHD2 gene. These and other CHD2 gene mutations either prevent the production of any chromodomain DNA helicase protein 2 or lead to the production of a nonfunctional version of the protein. As a result, chromatin remodeling and gene expression normally regulated by the chromodomain DNA helicase protein 2 are disrupted. It is unclear why CHD2 gene mutations seem to only affect nerve cells in the brain or how they lead to the signs and symptoms of CHD2 myoclonic encephalopathy.

Autism spectrum disorder

At least nine CHD2 gene mutations have been identified in people with autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. Mutations in the CHD2 gene impair the function of the CHD2 protein, resulting in small changes in the expression of many genes, the effects of which combine to affect brain development and increase the risk of ASD. Normal variations in other genes, as well as environmental risk factors, such as parental age, birth complications, and others that have not been identified, also affect an individual's risk of developing this complex condition.

Lennox-Gastaut syndrome

MedlinePlus Genetics provides information about Lennox-Gastaut syndrome

Other Names for This Gene

• ATP-dependent helicase CHD2
• CHD-2
• EEOC
• FLJ38614

Genomic Location

Normal Function

The CHD8 gene provides instructions for making a protein that regulates gene activity (expression) by a process known as chromatin remodeling. Chromatin is the complex of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. When DNA is tightly packed, gene expression is lower than when DNA is loosely packed. Chromatin remodeling is one way gene expression is regulated during development.

The CHD8 protein is thought to affect the expression of many other genes that are involved in brain development before birth. In particular, the CHD8 protein and the genes it regulates likely help control the development of neural progenitor cells, which give rise to nerve cells (neurons), and the growth and division (proliferation) and maturation (differentiation) of neurons. In this way, the CHD8 protein helps to control the number of neurons in the brain and prevent overgrowth.

Health Conditions Related to Genetic Changes

Autism spectrum disorder

More than 30 CHD8 gene mutations have been identified in people with autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. Mutations in the CHD8 gene impair the function of the CHD8 protein, and may interfere with its ability to help control the number and growth of neurons in the brain. Excess neurons and overgrowth in parts of the brain are associated with ASD, but the relationship between these abnormalities and the behavioral features of the disorder is unknown.

Other Names for This Gene

• ATP-dependent helicase CHD8
• AUTS18
• axis duplication inhibitor
• chromodomain-helicase-DNA-binding protein 8 isoform 1
• chromodomain-helicase-DNA-binding protein 8 isoform 2
• duplin
• helicase with SNF2 domain 1
• HELSNF1
• KIAA1564

Genomic Location

Normal Function

The DYRK1A gene provides instructions for making an enzyme that is important in the development of the nervous system. The DYRK1A enzyme is a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. Phosphorylation of proteins helps to control (regulate) their activity.

The proteins whose activity the DYRK1A enzyme helps regulate are involved in various processes in cells, including cell growth and division (proliferation) and the process by which cells mature to carry out specific functions (differentiation). In nerve cells (neurons), the DYRK1A enzyme is involved in the formation and maturation of dendritic spines from dendrites. Dendrites are specialized extensions from neurons that are essential for the transmission of nerve impulses. Dendritic spines are small outgrowths from dendrites that further help transmit nerve impulses and increase communication between neurons.

Health Conditions Related to Genetic Changes

Autism spectrum disorder

At least 11 DYRK1A gene mutations have been identified in people with autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. Most people with ASD associated with DYRK1A gene mutations also have other signs and symptoms. In some cases, they have a particular combination of additional features, including intellectual disability, speech problems, anxiety, and an unusually small head (microcephaly). Other signs and symptoms that may occur in these individuals include recurrent seizures (epilepsy), characteristic facial features, weak muscle tone (hypotonia), foot abnormalities, and walking problems (gait disturbance). This pattern of signs and symptoms is sometimes called DYRK1A-related intellectual disability syndrome.

DYRK1A gene mutations result in loss of the DYRK1A enzyme or an enzyme that does not function properly. Impaired or absent DYRK1A enzyme function likely leads to abnormal regulation of gene expression and disrupts proper neural development. However, the specific relationship between DYRK1A gene mutations and the signs and symptoms of ASD, as well as the other features that may occur in people with these mutations, is unclear.

Other Names for This Gene

• dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A
• dual specificity YAK1-related kinase
• DYRK
• DYRK1
• HP86
• MNB
• mnb protein kinase homolog hp86
• MNB/DYRK protein kinase
• MNBH
• MRD7
• protein kinase minibrain homolog
• serine/threonine kinase MNB
• serine/threonine-specific protein kinase

Genomic Location

Normal Function

The POGZ gene provides instructions for making a protein that is found in the cell nucleus. The POGZ protein is part of a group known as zinc finger proteins, which contain one or more short regions called zinc finger domains. These regions include a specific pattern of protein building blocks (amino acids) and one or more charged atoms of zinc (zinc ions). The folded configuration of the zinc finger domain stabilizes the protein and allows it to attach (bind) to other molecules.

In the cell nucleus, the POGZ protein attaches (binds) to chromatin, which is the network of DNA and proteins that packages DNA into chromosomes. Binding of the POGZ protein is part of the process that changes the structure of chromatin (chromatin remodeling) to alter how tightly regions of DNA are packaged. Chromatin remodeling is one way gene activity (expression) is regulated; when DNA is tightly packed gene expression is lower than when DNA is loosely packed. Regulation of gene expression by the POGZ protein is thought to be important to brain development, but the specific function of POGZ in the brain is not well understood.

Health Conditions Related to Genetic Changes

White-Sutton syndrome

At least 17 POGZ gene mutations have been found to cause White-Sutton syndrome. This disorder is characterized by intellectual disability, specific facial features, and other signs and symptoms affecting various parts of the body, particularly vision problems and gastrointestinal problems. Most affected individuals have features of autism spectrum disorder (ASD), a varied condition characterized by impaired social skills, communication problems, and repetitive behaviors. POGZ gene mutations are thought to impair the ability of the POGZ protein to bind to chromatin, leading to abnormal gene expression that affects development of the brain and other body systems. However, little is known about the specific changes in gene expression and how they lead to the development of intellectual disability and other signs and symptoms of White-Sutton syndrome.

Autism spectrum disorder

POGZ gene mutations have also been identified in people with ASD without other typical features of White-Sutton syndrome (described above). While the exact disease mechanism is unknown, studies suggest that the POGZ gene mutations associated with ASD result in a POGZ protein with impaired ability to bind to chromatin. Lack of chromatin binding likely results in abnormal chromatin remodeling, altering the normal expression of genes involved in brain development and leading to ASD. It is unclear why POGZ gene mutations lead to White-Sutton syndrome in some individuals and ASD without additional signs and symptoms in others.

Other Names for This Gene

• KIAA0461
• MRD37
• putative protein product of Nbla00003
• WHSUS
• zinc finger protein 280E
• zinc finger protein 635
• ZNF280E
• ZNF635
• ZNF635m

Genomic Location

Normal Function

The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme attaches (binds) to another PTEN enzyme (dimerizes) then binds to the cell membrane. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of a cluster of oxygen and phosphorus atoms. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell proliferation that can lead to the formation of tumors.

Health Conditions Related to Genetic Changes

Bannayan-Riley-Ruvalcaba syndrome

More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered together as PTEN hamartoma tumor syndrome (described below).

Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba syndrome results from the deletion of a large amount of genetic material that includes part or all of the PTEN gene. All of these genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth and the formation of hamartomas and other types of tumors. Research is needed to determine what role PTEN gene mutations play in causing macrocephaly and the other features of Bannayan-Riley-Ruvalcaba syndrome.

Breast cancer

Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of Cowden syndrome (described below). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called trastuzumab (Herceptin), which is used to treat breast cancer.

Cowden syndrome

Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing certain cancers, particularly breast cancer (described above), thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below).

Mutations that cause Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which contributes to the development of hamartomas and cancerous tumors.

Autism spectrum disorder

PTEN gene mutations have been identified in several people who have both an unusually large head size and the characteristic features of autism spectrum disorder, which affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the PTEN enzyme or lead to the production of an abnormally short version of the enzyme. Researchers are studying how changes in the PTEN gene are related to the risk of developing autism spectrum disorder. Some of these mutations have also been reported in families with PTEN hamartoma tumor syndrome (described below), and it is unclear how these mutations can cause different disorders.

Prostate cancer

Studies suggest that somatic mutations in the PTEN gene may be the most frequent genetic changes in prostate cancer. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other disorders

Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome (described above), are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors.

In some published case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a clinical diagnosis of Proteus syndrome. Instead, these individuals have a condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Other cancers

Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Other Names for This Gene

• MMAC1
• mutated in multiple advanced cancers 1
• phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
• phosphatase and tensin homolog deleted on chromosome 10
• protein-tyrosine phosphatase PTEN
• PTEN-MMAC1 protein
• PTEN1
• PTEN_HUMAN
• TEP1
• TEP1 phosphatase

Genomic Location

Normal Function

The RELN gene provides instructions for making a protein called reelin. This protein is produced in the brain both before and after birth. Reelin is released by certain brain cells. After being released, it attaches (binds) to specific receptor proteins. In the developing brain, this binding turns on (activates) a signaling pathway that triggers nerve cells (neurons) to migrate to their proper locations.

After birth, reelin likely plays a role in many brain processes, including the extension of axons and dendrites, which are specialized outgrowths from nerve cells that are essential for the transmission of nerve impulses. Reelin may also regulate synaptic plasticity, which is the ability of connections between neurons (synapses) to change and adapt over time in response to experience. Additionally, reelin controls the release of chemicals that relay signals in the nervous system (neurotransmitters).

Health Conditions Related to Genetic Changes

Autosomal dominant epilepsy with auditory features

Variants (also called mutations) in the RELN gene can cause autosomal dominant epilepsy with auditory features (ADEAF). People with this rare form of epilepsy typically hear sounds, like buzzing or humming, during seizures.

RELN gene variants associated with ADEAF reduce the amount of reelin in the body. Research suggests that a shortage of reelin impairs the formation or function of synapses, where cell-to-cell communication occurs. Abnormal communication between neurons can lead to seizure activity in the brain.

Lissencephaly with cerebellar hypoplasia

Several variants in the RELN gene have been found to cause lissencephaly with cerebellar hypoplasia (LCH). This condition affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the brain region involved in coordinating movements is unusually small and underdeveloped (cerebellar hypoplasia).

The RELN gene variants that cause LCH lead to a complete lack of reelin. As a result, the signaling pathway that triggers neuronal migration is not activated. Without reelin, neurons are disorganized, the normal folds and grooves of the brain do not form, and brain structures do not develop properly. This leads to intellectual disabilities, delays in overall development, movement problems, and other signs and symptoms of LCH.

Autism spectrum disorder

Certain genetic changes that reduce but do not eliminate the production of reelin may increase a person's risk of autism spectrum disorder, a condition that affects communication and social interaction. However, some studies have not supported these findings. Many genetic and environmental factors are believed to contribute to this complex condition.

Myoclonus-dystonia

MedlinePlus Genetics provides information about Myoclonus-dystonia

Other disorders

Studies have shown that certain variations (polymorphisms) in the RELN gene are associated with an increased risk of psychiatric disorders such as schizophrenia and bipolar disorder. Women with these polymorphisms are at particular risk of developing bipolar disorder. However, many genetic and environmental factors likely contribute to the development of these complex conditions.

Other Names for This Gene

• LIS2
• PRO1598
• RELN_HUMAN
• RL

Genomic Location

Normal Function

The SHANK3 gene provides instructions for making a protein that is found in many of the body's tissues but is most abundant in the brain. The SHANK3 protein plays a role in the functioning of synapses, which are the connections between nerve cells (neurons) where cell-to-cell communication occurs. Within synapses, the SHANK3 protein acts as a scaffold that supports the connections between neurons, ensuring that the signals sent by one neuron are received by another.

The SHANK3 protein is also involved in the formation and maturation of dendritic spines. Dendrites are specialized extensions from neurons that are essential for the transmission of nerve impulses. Dendritic spines are small outgrowths from dendrites that further help transmit nerve impulses and increase communication between neurons.

Health Conditions Related to Genetic Changes

22q13.3 deletion syndrome

The characteristic signs and symptoms of 22q13.3 deletion syndrome, which is also commonly known as Phelan-McDermid syndrome, are caused by a deletion near the end of the long (q) arm of chromosome 22. The chromosomal region that is typically deleted is thought to contain many genes, including the SHANK3 gene. As a result of the deletion, people with this condition have only one copy of the SHANK3 gene in each cell instead of the usual two copies.

Researchers believe that a deletion of the SHANK3 gene and a reduction in the amount of SHANK3 protein produced is responsible for many of the features of 22q13.3 deletion syndrome. A decrease in the functioning of synapses and cell-to-cell communication between neurons caused by a lack of SHANK3 protein is thought to contribute to the developmental delay, intellectual disability, and absent or severely delayed speech characteristic of people with 22q13.3 deletion syndrome.

Autism spectrum disorder

At least 43 SHANK3 gene mutations have been found in people who have autism spectrum disorder (ASD), which is a varied condition characterized by impaired communication and socialization skills, as well as repetitive behaviors. Most of these mutations disrupt the function of the SHANK3 protein or prevent the protein from being produced. It is unclear how changes in the SHANK3 gene are related to the risk of developing ASD. Researchers suspect that a disruption in communication between neurons contributes to the development of this condition. Variations in other genes and environmental factors are also thought to affect the risk of this complex disorder.

Other Names for This Gene

• proline-rich synapse-associated protein 2
• ProSAP2
• SPANK-2

Genomic Location

Normal Function

The SYNGAP1 gene provides instructions for making a protein, called SynGAP, that plays an important role in nerve cells in the brain. SynGAP is found at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Connected nerve cells act as the "wiring" in the circuitry of the brain. Synapses are able to change and adapt over time, rewiring brain circuits, which is critical for learning and memory. SynGAP helps regulate synapse adaptations and promotes proper brain wiring. The protein's function is particularly important during a critical period of early brain development that affects future cognitive ability.

Health Conditions Related to Genetic Changes

SYNGAP1-related intellectual disability

At least 40 mutations in the SYNGAP1 gene have been found to cause SYNGAP1-related intellectual disability. In addition to mild-to-moderate intellectual disability, this condition commonly features other neurological problems, including recurrent seizures (epilepsy) and autism spectrum disorder, which affects communication and social interaction.

Gene mutations involved in SYNGAP1-related intellectual disability prevent the production of functional SynGAP protein from one copy of the gene, reducing the protein's activity in cells. Studies show that a reduction of SynGAP activity can have multiple effects in nerve cells, including pushing synapses to develop (mature) too early. The changes triggered by a reduction of SynGAP activity disrupt the synaptic adaptations in the brain that underlie learning and memory, leading to cognitive impairment and other neurological problems characteristic of SYNGAP1-related intellectual disability.

Autism spectrum disorder

At least five SYNGAP1 gene mutations have been identified in people with autism spectrum disorder (ASD), a condition that appears early in childhood development, varies in severity, and is characterized by impaired social skills, communication problems, and repetitive behaviors. These mutations result in a SynGAP protein with impaired function or prevent the production of the protein. Changes in synaptic adaptation in individuals with these mutations may underlie the behavioral abnormalities characteristic of ASD. It is not known why some people with SYNGAP1 gene mutations develop ASD while others have the additional features of SYNCAP1-related intellectual disability (described above).

Other Names for This Gene

• KIAA1938
• MRD5
• neuronal RasGAP
• Ras GTPase-activating protein SynGAP
• ras/Rap GTPase-activating protein SynGAP
• RASA5
• synaptic Ras GTPase activating protein 1 homolog
• synaptic Ras GTPase activating protein, 135kDa
• synaptic Ras GTPase-activating protein 1
• SYNGAP

Genomic Location

Normal Function

The UBE3A gene provides instructions for making a protein called ubiquitin protein ligase E3A. Ubiquitin protein ligases are enzymes that target other proteins to be broken down (degraded) within cells. These enzymes attach a small molecule called ubiquitin to proteins that should be degraded. Cellular structures called proteasomes recognize and digest these ubiquitin-tagged proteins. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.

Studies suggest that ubiquitin protein ligase E3A plays a critical role in the normal development and function of the nervous system. Studies suggest that it helps control (regulate) the balance of protein synthesis and degradation (proteostasis) at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Regulation of proteostasis is important for the synapses to change and adapt over time in response to experience, a characteristic called synaptic plasticity. Synaptic plasticity is critical for learning and memory.

People normally inherit two copies of the UBE3A gene, one from each parent. Both copies of the gene are turned on (active) in most of the body's tissues. However, in nerve cells (neurons) in the brain and spinal cord (the central nervous system), only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation results from a phenomenon known as genomic imprinting.

Health Conditions Related to Genetic Changes

Angelman syndrome

A loss of UBE3A gene function in the brain likely causes many of the characteristic features of Angelman syndrome, a complex genetic disorder that primarily affects the nervous system. This loss of function results from a chromosomal change or gene variant (also known as a mutation) that affects the maternal copy of the gene.

Several different genetic mechanisms can turn off (inactivate) or delete the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In another 10 to 20 percent of cases, Angelman syndrome results from variants within the UBE3A gene itself. Most of these variants lead to the production of an abnormally short, nonfunctional version of ubiquitin protein ligase E3A. Because the copy of the gene inherited from a person's father (the paternal copy) is normally inactive in most areas of the brain, loss of the maternal copy prevents any of the enzyme from being produced in these brain regions. This lack of enzyme function likely causes the major signs and symptoms of Angelman syndrome.

Other abnormalities involving the region of chromosome 15 that contains the UBE3A gene can also cause Angelman syndrome. These chromosomal changes include rearrangements (translocations) of genetic material or a defect in the region of DNA that controls activation of the UBE3A gene. Like variants within the gene, these chromosomal changes prevent any functional ubiquitin protein ligase E3A from being produced in certain parts of the brain.

Other disorders

Variants in the UBE3A gene have been found in a small number of individuals with a variety of neurological problems, including intellectual disability, seizures, and autism spectrum disorder. Unlike variants involved in Angelman syndrome, which reduce the function of ubiquitin protein ligase E3A in cells, these rare variants increase the function of the protein. It is not clear how excess ubiquitin protein ligase E3A activity affects development and contributes to the neurological features in people with these variants.

Other Names for This Gene

• ANCR
• CTCL tumor antigen se37-2
• E6-AP
• E6AP ubiquitin-protein ligase
• EPVE6AP
• HPVE6A
• human papilloma virus E6-associated protein
• oncogenic protein-associated protein E6-AP
• UBE3A_HUMAN
• ubiquitin protein ligase E3A (human papilloma virus E6-associated protein, Angelman syndrome)

Genomic Location

ASD has a tendency to run in families, but the inheritance pattern is usually unknown. People with gene changes associated with ASD generally inherit an increased risk of developing the condition, rather than the condition itself. When ASD is a feature of another genetic syndrome, it can be passed on according to the inheritance pattern of that syndrome.

The symptoms of one person with autism can be very different from the symptoms of another person with autism. Health care providers think of autism as a spectrum disorder—which means that there is a range of similar features in different people with the disorder.

One person with autism may have mild symptoms, while another may have more serious symptoms, but they both have autism spectrum disorder (ASD).

Despite the range of possible symptoms, there are certain actions and behaviors that are common in ASD and could signal that a child is on the autism spectrum. Parents and caregivers who notice these "red flags" should speak to their child's health care provider about autism and screening the child for ASD.

In general, the main signs and symptoms of ASD relate to:

• Communication and interactions with other people
• Routines or repetitive behaviors, sometimes called stereotyped (pronounced STER-ee-uh-tahypt) behaviors

Health care providers organize some noticeable symptoms of autism into "red flags" to help parents and caregivers know what to look for as children grow and develop. These red flags are listed below.

Red Flags for ASD

Communication

• Does not respond to his/her name by 12 months of age
• Cannot explain what he/she wants
• Doesn't follow directions
• Seems to hear sometimes, but not other times
• Doesn't point or wave "bye-bye"
• Used to say a few words or babble, but now does not

Social Behavior

• Doesn't smile when smiled at
• Has poor eye contact
• Seems to prefer to play alone
• Gets things for him/herself only
• Is very independent for his/her age
• Seems to be in his/her "own world"
• Seems to tune people out
• Is not interested in other children
• Doesn't point out interesting objects by 14 months of age
• Doesn't like to play "peek-a-boo"
• Doesn't try to attract his/her parent's attention

Stereotyped Behavior

• Gets "stuck" doing the same things over and over and can't move on to other things
• Shows unusual attachments to toys, objects, or routines (for example, always holding a string or having to put on socks before pants)
• Spends a lot of time lining things up or putting things in a certain order
• Repeats words or phrases (sometimes called echolalia [pronounced ek-oh-LEY-lee-uh])

Other Behavior

• Doesn't play "make believe" or pretend by 18 months of age
• Has odd movement patterns
• Doesn't know how to play with toys
• Does things "early" compared to other children
• Walks on his/her toes
• Doesn't like to climb on things such as stairs
• Doesn't imitate silly faces
• Seems to stare at nothing or wander around with no purpose
• Throws intense or violent tantrums
• Is overly active, uncooperative, or resistant
• Seems overly sensitive to noise
• Doesn't like to be swung or bounced on his/her parent's knee, etc.

You can find age-specific milestones on the Centers for Disease Control and Prevention website Learn the Signs. Act Early. If your child does not meet developmental milestones, talk to his or her health care provider about screening for ASD.

Note about these red flags:

• Some of these red flags apply only at certain ages, so consider what is typical for other children your child's age.
• Some red flags are more strongly associated with autism than others.
• If your child shows any red flags for autism, talk to his or her health care provider.

The behavioral symptoms of autism spectrum disorder (ASD) often appear early in development. Many children show symptoms of autism by 12 months to 18 months of age or earlier. Some early signs of autism include:

• Problems with eye contact
• No response to his or her name
• Problems following another person's gaze or pointed finger to an object (or "joint attention")
• Poor skills in pretend play and imitation
• Problems with nonverbal communication

Many parents are not aware of these "early" signs of autism and don't start thinking about autism until their children do not start talking at a typical age.

Most children with autism are not diagnosed until after age 3, even though health care providers can often see developmental problems before that age.

Research shows that early detection and early intervention greatly improve outcomes, so it's important to look for these symptoms when a child is as young as possible.

Regression

Some children with autism regress, meaning they stop using language, play, or social skills that they've already learned. This regression may happen between ages 1 year and 2 years. It might happen earlier for some social behaviors, such as looking at faces and sharing a smile. Researchers don't know why some children regress into autism or which children are likely to regress.

Other Early Signs

There also may be early biological signs of ASD. Recent studies have shown that:

• People with autism have unique brain activity, structures, and connections even at very young ages.
• There are differences in brain growth in ASD as early as 6 months of age.

For many children, symptoms improve with age and behavioral treatment. During adolescence, some children with ASD may become depressed or experience behavioral problems, and their treatment may need some modification as they transition to adulthood. People with ASD usually continue to need services and supports as they get older, but depending on severity of the disorder, people with ASD may be able to work successfully and live independently or within a supportive environment.

Health care providers look for certain symptoms or groups of symptoms to diagnose autism spectrum disorder (ASD). If you have concerns about your child's development, talk to his or her health care provider right away. The provider then can examine the child and check for specific problems, such as autism.

Routine Developmental Screening

Your child's health care provider will check for problems with your child's development at every well-baby and well-child visit, even if you don't report any of the signs of autism or other problems. In addition, the American Academy of Pediatrics recommends that health care providers administer an ASD-specific tool to assess development at the 18-month and 24-month visits regardless of whether the child has risk factors for ASD.

During these developmental screenings, the health care provider may:

• Ask you specific questions about your child's actions and behavior
• Ask you to fill out a questionnaire about your child's behavior
• Speak directly to the child

Specialized Screening for ASD

The health care provider might use a screening test specifically for ASD. This test might be the Checklist of Autism in Toddlers (CHAT), the Modified Checklist for Autism in Toddlers (M-CHAT), or another test.

In addition, the health care provider may also recommend that your child have a blood test to help rule out some other conditions and problems.

Depending on the results of the blood test and the developmental and other screenings, your child's health care provider will either:

• Rule out autism or
• Refer your child to a specialist in child development or another specialized field to diagnose the child with autism. The specialist will then do a number of tests to figure out whether your child has autism or another condition. These will include tests of your child's communication abilities and observation of the child's behaviors.

Because the diagnostic criteria for ASD changed in 2013 (see below), ongoing research will help ensure that these screening tests are accurately identifying children who meet the new criteria for ASD.

Diagnosing ASD

The American Psychiatric Association, a professional society of psychiatrists, updated the criteria for an autism diagnosis in May 2013. The criteria are published in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

According to the DSM-5 criteria, a person has ASD if he or she:

• Has problems with communication and social interactions, namely:
  • Doesn't respond appropriately to social and emotional cues
  • Has deficits in nonverbal communication during social interactions
  • Has trouble developing friendships, keeping friends, and understanding relationships
• Has at least two types of repetitive behavioral patterns. These might include repetitive movements, inflexible routines, very restricted interests, or unusual responses to certain sensory inputs, such as the way a particular object feels.

There are various tools that specialists commonly use to diagnose autism. The only tool that currently fits the revised DSM-5 criteria is the Autism Diagnostic Observation Schedule (ADOS-2). However, it alone is not enough to make a diagnosis of ASD. Existing diagnostic tools are being modified to better fit the DSM-5 criteria.

During an ADOS-2 assessment, the specialist interacts directly with your child in social and play activities. For example, the specialist will see whether your child responds to his or her name and how he or she performs in pretend play, such as with dolls. The specialist is looking for specific characteristics that are hallmarks of ASD. To be diagnosed with ASD, a child must have had symptoms since an early age.

As part of the diagnosis, the specialist will also note whether your child has:

• Any genetic disorder that is known to cause ASD or its symptoms, including Fragile X syndrome or Rett syndrome; your child might receive a genetic test to detect these types of disorders.
• A language disability and the level of disability
• Intellectual disability and the level of disability
• Any medical conditions common among those with ASD, such as seizures, anxiety, depression, or problems with the digestive system

Depending on your child's unique symptoms and needs, the team of specialists may also want to give your child a range of other tests. If your child shows symptoms of seizures, a brain specialist, or neurologist, might use electrical sensors to observe your child's brain activity.

Your child may need other tests to determine how best to treat the symptoms of ASD. A hearing specialist, or audiologist, might test your child's hearing, which can sometimes seem poor in children with ASD. Other tests might include tests of muscle strength and tests of your child's ability to control movement.