Basic genetics
Chromosomes are packages of genetic information (or genes) found in the cells of the body. We typically have 46 chromosomes that come in 23 pairs. The first 22 pairs are the same for males and females and the 23rd pair are our sex chromosomes; females usually have two X chromosomes and males usually have an X and a Y chromosome.
Genes are the instructions, much like a recipe, that tell our bodies how to grow, develop and function. Genes come in pairs and we inherit two copies of most genes, one from each parent. The exception is for some genes on the X chromosomes for males as they only inherit one copy of those genes from the mother.
A genetic test is a type of test that is usually done on a blood sample to identify changes in genetic information (chromosomes, genes or proteins).
Find more information about chromosomes, genes and inheritance in How the Body Works: Genetics.
Indications of genetic testing in children with epilepsy
Not every child with epilepsy needs a genetic test. Genetic testing is usually performed in the following situations:
- very early onset epilepsy (starting in the newborn period or early infancy)
- absence of acquired cause of brain injury on clinical evaluation and MRI
- presence of drug-resistant epilepsy
- presence of developmental delay along with epilepsy
- presence of dysmorphic features along with epilepsy
Why is genetic testing necessary for some children with epilepsy?
There are several advantages of knowing the underlying genetic cause of your child’s epilepsy. These include:
- better understanding of your child’s condition
- determine the potential for targeted therapy for their genetic abnormality, also known as precision medicine
- know which anti-seizure medications may benefit your child, and which may be harmful for their genetic condition
- knowledge about other medical risks and conditions which may be known to occur with the genetic condition, so that these can be looked for and treated
- understand the prognosis and long-term outcomes
- help reduce additional invasive tests or procedures, such as surgical work up
- determine whether family members should be tested
- help to make informed reproductive choices and access options such as prenatal diagnostic and/or preimplantation genetic testing
What happens during a genetic test?
Genetic testing involves analyzing a sample of your child’s blood to identify changes or abnormalities (also called mutations) in genes that may be linked to epilepsy. Sometimes, the testing may also be done in brain tissue, if your child has undergone a brain surgery or a brain biopsy. The results can take several weeks to months. Testing of parents is also performed frequently, sometimes along with the child’s genetic testing, or after viewing the child’s genetic test results.
Types of genetic testing
A chromosomal microarray is a genetic test that looks for extra (duplications) or missing (deletions) pieces of chromosomes.
A targeted gene sequencing panel is a set of genes known to be associated with epilepsy. Panels can test from a small number of genes to several hundred genes at once.
Whole exome sequencing (WES) is a broad genetic test that looks for genetic changes in sections of genes (called exons) that make instructions for proteins. Most of the changes in genes that cause health problems are found in the exome.
Whole genome sequencing (WGS) is a more comprehensive genetic test that looks for changes / abnormalities throughout the genome (genetic material of a person).
Mitochondrial DNA (mtDNA) testing is specific testing of the small amount of genetic material present in our mitochondria, which are the structures that produce energy in our cells. We inherit our mtDNA from our mothers.
Possible results of genetic testing
- Positive (pathogenic or likely pathogenic): the genetic cause of the symptoms has been found. A pathogenic variant is a genetic change that causes a condition or is associated with an increased chance for a condition. This may also be referred to as a mutation.
- Negative: no genetic cause for epilepsy has been found.
- Inconclusive: the results are of uncertain significance or do not explain the symptoms. A variant of uncertain significance (VUS) is a genetic change for which there is currently not enough information to determine if it is harmless (benign) or associated with health/developmental problems (pathogenic). Our understanding of a VUS can change over time as new information becomes available.
- Secondary or incidental finding: a genetic cause or risk for symptoms unrelated to the reason for testing has been found.
Parental testing is often required to interpret results of a child’s genetic testing. Sometimes the mutation is new in the affected child and is called ‘de novo’. A de novo genetic variant arises for the first time in one individual. Usually, this is caused by a random change in the DNA of the egg or the sperm cell of the parent but is not otherwise present in either parent.
Sometimes the mutation is inherited from a parent that does not have the same symptoms as the child. For some genetic conditions, not everyone with a disease-causing variant will develop the symptoms of the disease. This is called incomplete penetrance.
What types of genetic disorders are there?
There are different types of genetic disorders.
- Chromosomal disorders occur when entire chromosomes or parts of chromosomes are missing or changed. Chromosomal disorders can occur spontaneously or be inherited.
- Mendelian disorders occur when a single gene is not working properly. For some conditions, both copies of a gene are altered (autosomal recessive inheritance) while in other conditions a single change in a gene can result in epilepsy (autosomal dominant or X-linked inheritance). Single gene disorders can be inherited from a parent or be brand new in the affected individual. For more information about inheritance patterns see How the Body Works: Genetics
- Mitochondrial disorders can be inherited in an autosomal recessive pattern or can result from mutations in specific genetic material found in mitochondria and inherited from our mothers only.
- Multifactorial or complex disorders are related to mutations in multiple genes, often combined with an environmental influence. These disorders tend to cluster in families, and close relatives have an increased risk to develop epilepsy.
Precision medicine
Precision medicine is the emerging medical model of utilizing genetic results to target appropriate therapies for genetic epilepsies. Some current examples include treatment of tuberous sclerosis complex with mTOR inhibitors, pyridoxine-dependent epilepsy with vitamin B6 and glucose 1 transporter deficiency with ketogenic diet.
As health-care providers and researchers learn more about the genetic causes of epilepsy and their specific underlying pathophysiology, newer targeted treatments will continue to be discovered.
Epilepsy syndromes and genetic disorders
Genetic disorders can cause only epilepsy or epilepsy with other concerns often related to development or intellectual ability. The inheritance of epilepsy can be complex. For example:
- Two children with mutations in different genes may develop the same epilepsy syndrome.
- Two members of the same family with the same gene mutation may both develop epilepsy, but the features in each person may be very different.
- Some epilepsy syndromes are known to have a genetic basis, but the specific gene or genes that cause them to have not yet been identified.
- Some genetic conditions are not inherited but arise spontaneously through a new mutation in the affected child.
Many genes are involved in the complex formation of our brains. The changes in various genes needed for normal brain development can lead to seizures. Many other genes provide instructions for specific ion channels, which are how the cells in the brain (neurons) talk to each other. Changes in these genes can lead to seizure disorders. Also, our brains need lots of energy to function properly, so genetic conditions that impact energy production or inhibit the source of energy to our brains, can lead to seizures.
The following provides some examples of epilepsy syndromes that may result from genetic disorders. The field of epilepsy genetics is expanding rapidly, and new genes involved in epilepsy are identified frequently. For more detailed information on specific syndromes, please consult your child’s health-care provider or a genetic counsellor.
Chromosomal disorders
Changes in the chromosome number or structure lead to various types of chromosomal disorders. Some of these conditions have epilepsy as a feature along with other concerns.
Down syndrome (Trisomy 21)
Down syndrome is caused by an additional copy of chromosome 21. Instead of two copies of chromosome 21, individuals with Down syndrome have three copies. Approximately two per cent to 15 per cent of people with Down syndrome develop epilepsy.
Wolf-Hirschhorn syndrome
Wolf-Hirschhorn syndrome occurs when part of chromosome 4 is missing at 4p16.3. About 70 per cent of people with this condition have epilepsy.
Angelman syndrome
Angelman syndrome is caused by reduced function of a gene found on chromosome 15 ( 15q11.2-13). More than 80 per cent of people with this condition develop seizures, usually by age three.
Ring chromosome abnormalities
Ring chromosome abnormalities are rare disorders that occur when both ends of a chromosome are damaged and the chromosome reforms in a ring shape. Ring chromosome abnormalities, including ring chromosomes 6, 9, 14, 15, and 20, account for two to three per cent of cases of epilepsy, although not all people with these conditions have seizures.
Single gene epilepsy syndromes
Autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy is a syndrome in which brief focal seizures arising from the frontal lobes of the brain occur in clusters at night. Different gene mutations cause different versions of this syndrome. This syndrome usually appears when a child is around eight years old and can be mistaken for night terrors. The syndrome can be mild or severe in different family members, which means that health-care providers and families often fail to realize that the syndrome runs in the family. In most patients, the syndrome is mild and responds well to medication. Some mutations may arise spontaneously.
Self-limited familial neonatal epilepsy
Self-limited familial neonatal epilepsy usually presents with seizures on the second or third day after birth. Children with this syndrome have generalized clonic or tonic seizures. The seizures usually disappear after about one week. Approximately 11 per cent per cent of children with this syndrome go on to have seizures later in life. This syndrome is caused by one of several possible gene mutations.
Self-limited infantile familial epilepsy
Babies with self-limited infantile familial convulsions usually have clusters of focal seizures without fever, starting between the ages of four and eight months. The seizures are usually easy to control, and children do not generally have seizures later in life.
Early onset infantile developmental and epileptic encephalopathy (EIDEE)
The early onset, infantile developmental epileptic encephalopathies (EIDEE) are a group of disorders, characterized by an early onset, and difficult to treat seizures that have various genetic causes. They are often genetic but with ‘new’ (de novo) mutations. Affected children often have other features including global developmental delay, movement disorders, autism and behavioral issues.
Generalized epilepsy with febrile seizures plus
Generalized epilepsy with febrile seizures plus is caused by mutations to any of several different genes that affect two different ion channels. The syndrome causes various childhood-onset disorders, which can include febrile seizures, seizures without fever, focal epilepsy, myoclonic-astatic epilepsy, and severe myoclonic epilepsy in infancy.
KCNT1-related epilepsy
KCNT1-related epilepsy is most often associated with epilepsy of infancy with migrating focal seizures (EIMFS) or autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). KCNT1 is a potassium channel in the brain which are important for the ability of the brain to generate and transmit electrical signals. Some patients are the first affected person in their families given a new mutation. While other families may see multiple individuals with ADNFLE passed down in an autosomal dominant pattern.
KCNQ2-related epilepsy
Mutations in this gene have been identified in children with a spectrum of seizure disorders ranging from benign neonatal epilepsy at the mild end to neonatal epileptic encephalopathy at the severe end. Described patients tend to have early onset seizures which can resolve but continue to have developmental delays. KCNQ2 is a potassium channel in the brain, important for the ability of the brain to generate and transmit electrical signals.
POLG-related disorder
POLG is required for normal functioning of the mitochondria and this condition leads to problems with energy production. Symptoms can range from severe with early age of onset (intractable seizures, liver failure), to milder with presentation in adulthood with mainly eye-related issues.
PNPO
Pyridoxal 5'-phosphate-dependent epilepsy is a condition that involves seizures beginning soon after birth or, in some cases, before birth. The seizures typically involve irregular involuntary muscle contractions (myoclonus), abnormal eye movements and convulsions. Most babies with this condition are born prematurely.
SCN1A-related disorders
The SCN1A-related disorders encompass a spectrum of seizure disorders which range from simple febrile seizures and generalized epilepsy with febrile seizures at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic clonic seizures at the severe end. It is not possible to predict, given the mutation, what the severity of the seizure disorder will be, and it can be variable amongst family members with the same mutation.
STXBP1-related disorder
Changes in the STXBP1 gene have been associated with early infantile epileptic encephalopathy (EIEE). The STXBP1 gene encodes a syntaxin binding protein 1 and patients with mutations in one copy of this gene have been described to have various types of seizures, developmental delay, tremor, weak muscles and brain changes on MRI.
Tuberous sclerosis complex (TSC)
Tuberous sclerosis complex (TSC) is a condition in which benign tumours develop in the skin, brain, kidney and heart. Approximately 80 per cent of people with TSC develop epilepsy. Mutations in one of two genes, TSC1 or TSC2 cause TSC. TSC is inherited in an autosomal dominant fashion however about two-thirds of the mutations arise spontaneously (de novo).
Fragile X syndrome
Fragile X syndrome is caused mutation in the FRAX gene on the X chromosome. It usually affects boys more severely than girls and leads to mild to severe intellectual disability. Approximately 20 per cent to 40 per cent of people with the condition will also develop epilepsy.
Rett syndrome
Rett syndrome is caused, by mutations in the MECP2 gene on the X chromosome. In a few families, the syndrome is inherited in an X-linked dominant pattern. It was initially believed that Rett syndrome affects only girls; however, it has recently been found to occur very rarely in boys as well. The disorder usually develops between one and two years of age. Children with the disorder have epilepsy in 70 per cent to 80 per cent of cases, together with other problems such as constant handwringing, difficulty walking, developmental disability and autism.
Mitochondrial disorders
Mitochondrial disorders occur when the mitochondria are unable to produce enough energy for normal functioning in organs with high demands such as the brain, heart, liver, skeletal muscles, eyes and kidney. Mitochondrial disorders can present with muscle weakness, poor growth, heart failure due to cardiomyopathy, gastrointestinal disorders, liver disease and diabetes.
Myoclonus epilepsy and ragged-red fibres (MERRF)
Myoclonus epilepsy and ragged-red fibres (MERRF) is a progressive myoclonus epilepsy that is caused by a mutation in the mitochondrial DNA. People with this syndrome manifest it in a wide variety of ways; some are unaffected, some develop epilepsy later in life and others develop severe, progressive epilepsy with dementia as children.
Multifactorial disorders
A number of epilepsy syndromes are thought to be multifactorial or complex disorders, in which genetic and environmental factors both seem to play a part. Many epilepsy syndromes in children are multifactorial. Several genetic abnormalities may be associated, and the inheritance is complex. Examples include:
- juvenile myoclonic epilepsy
- childhood absence epilepsy
- self-limited epilepsy with centro-temporal spikes
- self-limited epilepsy with autonomic features
Genetic testing is currently not recommended for these conditions.