Genetic Analysis of Epilepsies Flashcards
Single gene vs polygenetic epilepsies
Epilepsy associated with a single gene mutation (Mendelian or monogenic inheritance) is thought to occur in approximately 1–2% of patients with epilepsy. Up to 40% of epilepsies are thought to involve polygenic or complex genetic inheri- tance, involving multiple possibly interacting genes and/or environmental influences [1, 2]
Genetic generalized epilepsies (formerly idio- pathic generalized epilepsies), where generalized seizures are the predominant feature, show mostly complex inheritance. However, specific muta- tions have been associated with a variety of other epilepsy syndromes, most notably early-onset epileptic encephalopathies, syndromes associated with febrile seizures, several familial focal epi- lepsy syndromes, as well as symptomatic epi- lepsy syndromes, in which seizures are only part of a more widespread CNS disorder
Types of genetic changes implicated in the development of seizures and epilepsy
Small deletions, insertions, and point mutations can lead to problems in neuronal meta- bolism, network development, and membrane anynaptic signaling. Contiguous gene syndromes are microdeletions leading to loss of several neighboring genes. Chromosomal abnormalities involve larger deletions, duplications, and translo- cations, usually causing polygenic dysfunction and producing severe symptoms such as mental retar- dation and/or growth failure. These are most fre- quently found in epilepsy patients with coexisting multiple congenital abnormalities and/or intellec- tual disability. Most involve de novo parental germ-cell mutations, but familial rearrangements such as balanced translocations can occur. Once they reach a certain number, trinucleotide repeat expansions may also lead to diseases associated with epilepsy
Standard karyotyping and high-resolution chromosome analysis
Used to identify chromosomal abnormalities such as Trisomy 21 or ring chromosome 20
Array-comparative genomic hybridization (aCGH)
Can detect submicroscopic chromosomal rear- rangements (deletions or duplications, also called copy number variations or CNVs) and can inves- tigate multiple loci simultaneously
Molecular karotyping
Testing for patho- genic CNVs using aCGH and SNP arrays is also known as molecular karyotyping.
These tests identify CNVs that are felt to be causative in approximately 15–20% of patients with intellectual disability [5], and 8% of patients with early-onset epileptic encephalopathies [6], and are becoming widely used in these settings.
SNP arrays
Can assess known SNPs throughout the genome
Other genetic tests
Fluorescent in situ hybridization (FISH) and multiplex ligation probe amplification (MLPA)
Clinical validity and utility
Clinical validity describes the ability of a test to determine whether a person is or will become affected with a given disorder. Clinical utility of a test refers to the risks and benefits of a positive or negative test on patient care.
Clinical validity is determined by many fac- tors. Genetic testing may be performed in several types of laboratories. Clinical laboratories in the USA that are certified under the Clinical Labora- tory Improvement Act (CLIA) are required to meet federal quality standards. Tests can also be carried out in research laboratories, which do not require CLIA certification and perform analyses for research only. There is also direct-to-consumer genetic testing, usually ordered over the Internet for a fee. This has the advantage of easy access and privacy, but is not subject to the same quality control measures as clinical laboratories, and generally does not include genetic counseling or adequate epidemiological data about baseline genetic variation to assist with interpretation of the results [2].
The appropriate type of test must also be ordered, as a given test will miss changes that it is not designed to detect (a mutation in a given gene may not affect a test for a particular SNP or CNV but still contribute to a disease). For each test, a negative result is most definitive if a positive result was obtained from an affected family member. Additionally, the source of DNA affects the validity of a test. A germ-line mutation (in a sex cell) may be absent in a parent’s somatic cells (leading to negative genetic testing), but can still be pas- sed on to offspring. Somatic mosaicism (more than one genotype in the body) may lead to negative testing from one tissue and positive testing from another [2].
Clinical validity is also impacted by the sen- sitivity and specificity of the test and the type of genetic change that is identified. When a muta- tion in a single gene produces different epilepsy phenotypes in different individuals, this is refer- red to as variable expressivity and reduces the positive predictive value of the test. For example, missense mutations in SCN1A can be associated with phenotypes ranging from no seizures or simple febrile seizures (GEFS+) to severe epileptic encephalopathy (Dravet syndrome) [7].
Genetic (or locus) heterogeneity occurs when a single clinical phenotype can result from mutations in different genes (e.g., in GEFS+ due to different sodium and/or GABA receptor mutations), or when different genetic mecha- nisms can produce the same disease (e.g., IGE can show autosomal dominant or complex inheritance). Additionally, families with a given syndrome may not have mutations in any previ- ously identified genes. Patients without affected relatives are also less likely to have a mutation in previously identified genes [2]. In such cases, a positive result may be informative, but a negative result is not helpful clinically.
Reduced penetrance describes when individ- uals with a mutation remain unaffected. Pene- trance for AD epilepsy is usually approximately 70% [2]. This lowers the positive predictive value of testing and can present significant dif- ficulties in predictive testing in asymptomatic individuals. Also, gene–environment interactions may play a role in the expression of a trait. Each of these factors may lead to decreased clinical validity of a genetic test.
Factors affecting clinical utility
Clinical utility depends on the clinical validity of a test, but also on specific features of a given clinical situation. The relative risks and benefits of testing depend on the availability of an effective treatment, cost and accessibility of testing, severity of the disease, age of onset (particularly as it may affect reproductive choi- ces), family history and the implications of test- ing on other family members, and potential ethical, legal, and social implications of genetic testing. The Federal Genetic Information Non-Discrimination Act (GINA) passed in May 2008 prohibits discriminatory use of genetic information by employers and health insurers, but does not extend to life insurance, disability insurance, or long-term case insurance [8]. All of these issues should be addressed in pretest and posttest genetic counseling, and informed con- sent should be obtained before ordering a genetic test [2].
How can genetic testing be used in epilepsy?
Diagnostically and predictively
Diagnostic testing is done in a patient with epilepsy to clarify the diagnosis and/or prognosis, to save a patient from further evaluation/testing, and rarely to affect clinical management. It can also provide families with information about the risks of recurrence and can help with reproductive decision-making. Ideally, this testing may also lead to targeted therapy.
Predictive testing is performed to predict the onset of epilepsy in asymptomatic patients (usually offspring or siblings of patients with epilepsy). This also includes prenatal diagnostic testing.
Risk of epilepsy in relatives of patients with epilepsy are affected by…
The risk of epilepsy in relatives of patients with epilepsy is increased if there is an earlier age of onset (<35 years old), idiopathic epilepsy, an increased number of affected rela- tives, and if a parent is affected, particularly the mother [9]. Particularly for prenatal diagnostic testing, epilepsy risk is increased if a parent is a carrier of a balanced chromosomal translocation, if the mother is a carrier of an X-linked or mitochondrial mutation, if both parents are car- riers for an autosomal recessive condition, or if a parent carries an autosomal dominant disorder [1]. Many severe pediatric neurogenetic condi- tions result from de novo or spontaneous muta- tions. If parents have negative genetic testing, the risk of recurrence in future offspring is <1% and would likely be attributable to undetectable gonadal mosaicism [1].
Options for parents at high risk who desire additional children
Options for parents at high risk who desire additional children include adoption, use of a donor egg or sperm (depending on which parent carries the mutation), prenatal testing (chorionic villous sampling or amniocentesis), or preim- plantation genetic diagnosis (which require in vitro fertilization). Of note, for women carry- ing a mitochondrial mutation, the risk of recur- rence cannot be accurately predicted and prenatal testing is not accurate. The only way to guarantee avoidance of recurrence is the use of a donor egg [1].
How to determine appropriate genetic testing…
In order to perform appropriate genetic test- ing, a full history must be obtained, including a three-generation pedigree focused on seizures and other seizure mimics, neurodevelopmental and psychiatric conditions, ancestral origins, outcomes of all pregnancies, and consanguinity. Full neurologic examination, developmental assessment, and appropriate further testing such as EEG, MRI, and/or metabolic workup can also contribute to appropriate genetic counseling and test selection
Syndromes beginning in the first year of life
Syndromes with prominent febrile seizures
Idiopathic epilepsy syndrome
Idiopathic generalized epilepsies
Idiopathic epilepsy syndrome
Focal epilepsies
Idiopathic epilepsy syndrome
Progressive myoclonic epilepsies
Symptomatic epilepsy syndrome
Epilepsies related to cortical malformations
Symptomatic epilepsy syndrome
Other
Symptomatic epilepsy syndroe
