Epilepsy: When to Perform a Genetic Analysis
Genetic mechanisms play an important role in the pathophysiology of epilepsy. Mechanisms include genomic rearrangements (e.g., ring chromosomes, translocations, monosomies, and trisomies), copy number variants (CNVs; deletions or duplications involving one or more genes), and single-nucleotide alterations, resulting in missense, frameshift, or nonsense mutations. Methylation defects or uniparental disomy may also affect one region of DNA (e.g., Prader–Willi and Angelman syndromes), resulting in gain or loss of function of genes typically expressed only from the maternal or paternal copy. Modes of inheritance vary depending on the type of genetic abnormality.
Many single-gene models of epilepsy have been identified for both lesional and nonlesional epilepsy. The most notable are the channelopathies (e.g., SCN1A-associated Dravet syndrome [DS]). Other mechanisms include modulation of synaptic vesicle docking and release (e.g., STXBP1), cell signaling (e.g., CDKL5), and transcription factors (e.g., ARX). In other cases, the genetics are thought to be more complex, involving multiple genes or susceptibility loci with incomplete penetrance and phenotypic variability likely due to gene–gene interactions and environmental and epigenetic factors (e.g., the idiopathic generalized epilepsies).
Tools for genetic testing in epilepsy
There are a number of genetic testing techniques that can be used to evaluate patients for genetic causes of epilepsy. Table 22.1 outlines these tests and provides suggestions for when they are to be ordered.
When to perform genetic testing in epilepsy
Epilepsy in defined genetic syndromes
It is important to be able to recognize genetic syndromes in which epilepsy is a prominent feature, as the diagnosis may impact treatment and monitoring for other medical conditions (e.g., monitoring for long QT syndrome in Rett syndrome). Table 22.2 describes syndromes in which epilepsy is a prominent feature.
|Testing method||Description||Suggestions of when to use this test|
|Chromosomal microarray||Uses either single-nucleotide polymorphism (SNP) array or array-comparative genomic hybridization (using oligonucleotide probes). Evaluates targeted regions throughout the chromosomes for CNVs||Especially when epilepsy is seen in association with developmental delay, autism, and/or dysmorphisms. Can also be helpful in other idiopathic epilepsy syndromes|
|Single-gene sequencing||Evaluates for sequence alterations and whether they cause amino acid changes||When a specific genetic abnormality is suspected. For example, test SLC2A1 when GLUT1 deficiency is suspected.|
|Single-gene duplication/deletion analysis||Evaluates for CNV in a targeted gene||When sequencing is negative and abnormality in a specific gene is suspected. More sensitive than microarray in this case|
|Targeted mutation analysis||Sequencing looking for a specific mutation|
|Panels of genes associated with a disorder||Sequencing ± duplication/deletion testing for a panel of genes of interest||In disorders with many associated genes, such as the EOEEs|
|Methylation studies||Evaluates for methylation abnormalities in a specific chromosomal region||Suspected methylation disorders such as Prader–Willi and Angelman syndromes|
|Fluorescent in situ hybridization (FISH)||Fluorescently labeled probes identify specific chromosomal regions|
|Karyotype||A photographic representation of all of the chromosomes in a single cell, arranged in pairs based on size and banding pattern||Consider in patients with dysmorphisms or multiple congenital anomalies. May be helpful in the case of large CNVs to evaluate for rearrangements|
|Whole exome or whole genome sequencing||Evaluates for sequence changes and CNVs throughout the genome||Consider when known clinical testing is not revealing and a genetic diagnosis is strongly suspected|
CNVs, copy number variants; EOEEs, early-onset epileptic encephalopathies.
There are other syndromes that are suspected to be genetic in origin but for which we do not yet have an identified genetic etiology (e.g., myoclonic-atonic epilepsy).
Epilepsy in association with features that suggest a genetic syndrome
If there are dysmorphic features or congenital anomalies that do not fit a well-described syndrome, consider initiating genetic testing with a broad screen such as a chromosomal microarray and referring to a pediatric geneticist.
In addition, there are an increasing number of identified genetic causes of epilepsy with brain malformations with or without other syndromic features (Table 22.3). In lissencephaly and double cortex syndrome, testing does not directly affect treatment but confirms a diagnosis and can help with prognosis and genetic counseling. For polymicrogyria, identification of DiGeorge syndrome or Zellweger syndrome would affect other medical management, and the other genes would provide an explanation. For periventricular nodular heterotopia (PVNH), a FLNA mutation helps predict prognosis and suggest the need for screening for vascular defects. In the case of microcephaly and macrocephaly, each of the genes listed in Table 22.3 has a well-described phenotype, and knowing the diagnosis could be helpful for prognosis and management.
|Type of malformation||Associated genetic abnormalities|
|Lissencephaly or pachygyria||LIS1, ARX (males), DXC (males), RELN, TUBA1A|
|Double cortex||DXC (females)|
|Polymicrogyria||TUBA1A, TUBB2B, TUBB3, GPR56, DiGeorge syndrome (22q11.2 deletion), Zellweger syndrome (PEX1 and other PEX genes)|
|Microcephaly||CDKL5, FOXG1 (duplication), WDR62, ASPM, SLC25A22, PNKP (recessive mutations)|
|TSC with tubers and subependymal nodules||TSC1, TSC2|
PVNH, periventricular nodular heterotopia.
There are an increasing number of identified genetic causes of defined epilepsy syndromes including benign familial neonatal–infantile seizures (Table 22.4; see Chapter 20 for additional details on neonatal epilepsy syndromes), idiopathic generalized epilepsies, and benign focal epilepsies. For example, there are several “hot spots” for CNVs in idiopathic generalized or idiopathic focal epilepsies (e.g., 15q11.2, 15q13.3, 15q11-q13, 16p11.2, 16p13.11, 1q21.1). At times CNVs contain known epilepsy genes.
Mutations in SLC2A1 (Table 22.5) are associated with glucose transporter 1 (GLUT1) deficiency. Though typically early onset, it can be associated with other idiopathic generalized epilepsies. In addition to SCN1A and PCDH19, mutations or deletions in SCN1B, SCN2A, and GABRG2 are associated with genetic epilepsy with febrile seizures plus (GEFS+). Genes identified as susceptibility factors for generalized epilepsies include CACNA1H, CACNB4, CHRNA7, CLCN2, and EFHC1. CACNA1A is a gene associated with absence epilepsy and episodic ataxia.
Genetic testing for autosomal dominant nocturnal frontal lobe epilepsy has a fairly low yield (<10% for CHRNA4 and <5% for CHRNB2). Genetic testing for autosomal dominant partial epilepsy with auditory features (LGI1) may confirm the diagnosis, though if the family history is strongly suggestive it may not significantly affect management. It is not widely tested. De novo cases are rare. Indications to test for SYN1 are not fully developed. Genetic testing for benign rolandic epilepsy and for the other benign focal epilepsies is not typically indicated.
In these situations, the decision of whether or not to pursue genetic testing depends on a balance of clinical suspicion and benefit to the family. In some cases, a genetic diagnosis may be helpful in predicting outcome (such as with the benign familial neonatal–infantile seizures) or in genetic counseling for the family.
Early-onset epileptic encephalopathies (EOEEs)
The early-onset epileptic encephalopathies (EOEEs) include Ohtahara syndrome (OS), early myoclonic epilepsy (EME), nonspecific early-onset epileptic encephalopathy with burst–suppression (EOEE-BS), malignant migrating partial seizures in infancy (MMPEI), DS, and West syndrome (WS). With the exception of DS, which is most often associated with a mutation in SCN1A, the other syndromes are heterogeneous in etiology. OS is frequently associated with structural brain malformations but has also been associated with deletions or point mutations of the genes STXBP1 and SPTAN1. EME is often associated with metabolic etiologies, which are typically genetic in origin. Additional details of the EOEEs are provided in Chapters 20 and 21.