The Genetic Architecture of Epilepsy

4 May

Shivani Narasimhan

The last two decades have witnessed a surge in the process of unraveling genetic markers associated with Epipesies. Several unexpected findings have emerged, such as the significance of de novo mutations and the complexities of the genotype-phenotype relationships. This includes genetic heterogeneity, where one epilepsy syndrome may have multiple genetic causes, and pleiotropy, where a single gene can be linked to different phenotypes. In addition, the declining cost of genetic testing, along with the accessibility of whole exome or whole genome sequencing, is integrating genetics into routine epilepsy care.

The Genetic Landscape of Epilepsy

An estimated 30% of all epilepsy cases are believed to have a genetic origin. The International League Against Epilepsy (ILAE) defines genetic epilepsies as those directly resulting from a known genetic condition, where seizures are a primary symptom. Epilepsies can be classified as having a genetic basis in three ways: through family history, clinical research evidence, or when a genetic variant (including DNA sequence changes or larger chromosomal variations) is consistently associated with the epilepsy phenotype. According to ILAE, Genetic epilepsies include monogenic (inherited or de novo) or Complex (Polygenic) inheritance.

Molecular Mechanism of Genetic Epilepsy

The first genes linked to epilepsy, involving both de novo and inherited causes, were identified in those encoding subunits of neuronal ion channels. Mutations in these ion channel genes disrupt normal function, leading to seizures through either reduced inhibitory mechanisms or increased neuronal excitability. Ion channel genes fall into two main categories: voltage-gated and ligand-gated. Voltage-gated ion channels, such as SCN1A, SCN2A, KCNQ2, and CACNA1A, open in response to changes in membrane potential. Ligand-gated channels, like GABAA receptors, respond to chemical messengers and are crucial for inhibitory synaptic transmission. Variants in genes encoding GABAA receptor subunits, such as GABRA1 and GABRB3, are commonly associated with genetic epilepsies. In addition, studies have also revealed the role of multiple genes with an X-Linked inheritance pattern that contribute to the development of epilepsy. For instance, NEXMIF (involved in the nerve development), formerly known as KIAA2022, follows an X-linked dominant inheritance pattern and is associated with a broad phenotypic spectrum, affecting both males and females. Nearly all patients with pathogenic NEXMIF variants (99%) present with developmental/intellectual delays, and 83% experience seizures. This gene is an important contributor to epilepsy, reflecting the complexity of X-linked genetic disorders and their impact on neurological function. Another gene, ARX, inherited in an X linked recessive manner, has been implicated in Partington syndrome (Neurological condition that causes intellectual disability and movement disorders).

Inheritance patterns of Epileptic syndromes

Mendelian inheritance patterns in epilepsy, such as autosomal dominant, autosomal recessive, and X-linked, are rare but carry significant risks for relatives. In autosomal dominant disorders like benign familial neonatal epilepsy (BFNE) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), around 50% of first-degree relatives may inherit the mutated gene, with a high likelihood of clinical seizures (approximately 85% for BFNE and 70% for ADNFLE). Recessive epilepsies, often severe, like Lafora disease and Unverricht-Lundborg disease, pose a 25% risk for siblings, especially in consanguineous families. X-linked epilepsies vary depending on inheritance: X-linked recessive conditions affect boys (e.g., ARX-related epilepsies), while X-linked dominant disorders impact girls more severely. These distinctions are critical for genetic counseling.

The role of Genetic Testing in the identification of key Gene Variants

Recent advancements in genetic technologies have significantly transformed our understanding of epilepsy. Key mutations in ion channels (e.g. SCN1A, SCN2A), neurotransmitter receptors (e.g. GABRA1), and synaptic proteins (e.g. SYNGAP1, KCNQ2) have revealed critical pathways driving epilepsy susceptibility. Genome-wide association studies (GWAS) have linked variants near SCN1A and PCDH7 to epilepsy risk, improving diagnostic precision and enabling personalized treatment strategies. Epigenetic mechanisms like DNA methylation (MBD5), histone modifications (HDACs), and non-coding RNAs (e.g., miR-134) further modulate gene expression and synaptic plasticity, contributing to epileptogenesis. These discoveries are paving the way for tailored therapeutic interventions, with genetic testing now a key tool in clinical epilepsy management. In addition to the link between genetics and epigenetics, there is an intermediate domain called the “Endophenotypes” - heritable traits that include biochemical, endocrine, electrophysiological, cognitive, or anatomical aspects.

Genetic testing has revolutionized the diagnostic process for epilepsy by uncovering underlying causes that often remain undetected through conventional methods like clinical evaluations, EEGs, and brain imaging. This plays an integral role, especially in the diagnosis of rare epilepsies like Dravet syndrome, arising from mutations in the SCN1A gene. In addition, genetic testing is also able to identify mutations in the TBC1D24 gene and GABRA1 gene associated with autosomal dominant nocturnal frontal lobe epilepsy and genetic generalized epilepsy, respectively. This further demonstrates the usefulness of genetic testing in molecular analysis of Genetic Epilepsies.

Limitations of Genetic testing in Epilepsies

The NGS panels involved in the sequencing process are generally designed to focus on exons and the adjacent 20 base pairs of intronic regions, following clinical standards such as the ACMG guidelines. However, they often miss causative variants located in deep promoter or intronic regions. Additionally, NGS panels are typically unable to detect variable number tandem repeats (VNTRs), which are implicated in several monogenic epilepsies.

Future Directions

Recent research has shown that zebrafish serve as an effective model organism for epilepsy studies, given the strong similarity between human epilepsy-related genes and their zebrafish orthologs. Utilizing this model, along with other in vitro and in vivo methods, offers potential for functional testing of variants of unknown significance and drug screening, which may enhance diagnostic capabilities. Looking ahead, the future of epilepsy genetics is likely to see expanded use of whole genome sequencing (WGS) and integration of other -omics approaches, such as epigenomics, transcriptomics, and metabolomics, to deepen our understanding and improve treatment strategies.

Particularly, epigenomic changes, like DNA methylation and microRNA expression, may provide answers to many unresolved questions in epilepsy research. Environmental factors may significantly influence the disorder's progression through epigenetic modifications, contributing to the phenotypic and genetic diversity seen in epilepsy. However, given the disorder's complexity, it is unlikely that a single mechanism will emerge as the predominant cause.

References

N.E.T.A Institute