Rare epilepsy syndromes, often with early onset, can be caused by rare or unique single‐nucleotide variants (SNV), copy number variants (CNV), or chromosomal abnormalities. Common epilepsies, including most generalised and focal epilepsies, have a complex polygenic basis involving multiple small‐effect risk variants, with potential environmental contributions.

SINGLE‐NUCLEOTIDE VARIANTS

Recent technological advances and the increasing availability and sensitivity of next‐generation sequencing (NGS) technologies have brought significant progress in recognising genetic variants underlying early‐onset epilepsies. Identifying new genetic variants and assessing them in cellular and animal models allows for an understanding of the molecular roles and their pathogenic implications.

The first epilepsy‐causing gene variant in the alpha 4 subunit of the cholinergic receptor nicotinic (CHRNA4) was discovered in a hereditary form of epilepsy at the end of the twentieth century.¹ Currently, more than 1,000 genes are implicated as monogenic bases of epilepsy, as catalogued in the Genes4Epilepsy database.² Pathogenic variants are often located in protein‐coding sequences, causing amino acid substitutions (missense variants) or protein truncation (e.g. nonsense, frameshift, insertion–deletion, or splicing variants). Epilepsy variants can also affect non‐coding DNA (enhancers, promoters, terminators, transposable elements and repetitive DNA) and mitochondrial DNA. Demonstrating that a variant affects the function of the encoded protein, such as by directly impacting brain activity or development, supports its pathogenic role.

Epilepsies linked to single‐gene variants typically exhibit autosomal dominant inheritance patterns. Autosomal recessive or X‐linked inheritance occurs more rarely. Genes carrying variants often encode ion channels but also participate in diverse biological processes, including enzyme function, cytoskeletal dynamics, transporters or receptors, nucleic acid binding, cell adhesion, signal transduction and membrane trafficking. Phenotype–genotype correlation in monogenic conditions is complex, with broad phenotypic spectra for many implicated genes, incomplete penetrance and heterogeneous expression even within families carrying the same genotype.

Some gene panels utilise exome sequencing; however, the evaluation generated is limited to the genes included in the panel. Re‐interrogation for unexamined genes should be requested when appropriate. As the genetic landscape evolves with the discovery of new genes, exome sequencing is increasingly recommended when feasible.³ Genome sequencing, now entering clinical practice, enables the analysis of every gene across the genome, as well as intronic and regulatory regions.

Two classes of genetic variants are known: germline and somatic variants. Germline variants may be inherited or arise before zygote formation, and so affect every body cell. Somatic variants occur during postzygotic development and affect a subset of cells, with later‐occurring variants impacting fewer cells. Somatic variants are further classified into two categories: first‐hit and second‐hit variants. A first‐hit variant leads to a heterozygous mutation, while a second hit can result in a loss of heterozygosity.⁴ Targeted sequencing of resected brain tissue has highlighted the role of brain‐restricted somatic mosaic variants in genes of the mechanistic target of rapamycin (mTOR) pathway in malformations of cortical development, with variant allele frequencies as low as 0.01%.⁵

Developmental and epileptic encephalopathies (DEE) represent severe epilepsy syndromes usually presenting in childhood, with severe epilepsy and associated cognitive and behavioural impairments. Using NGS technologies, single‐gene germline pathogenic variants are identified in over half of the individuals with DEE.⁶ De novo variants cause most DEE, although some individuals have a parent with mosaicism, increasing the recurrence risk within families.⁷ While DEE are predominantly diagnosed in childhood by paediatric neurologists, many affected individuals transition to adult care, and genetic diagnoses continue to inform management, treatment, and prognosis.⁸

CHROMOSOMAL ABNORMALITIES AND COPY NUMBER VARIANTS (CNV)

Chromosomal abnormalities include deletions, duplications, translocations, inversions, ring chromosomes and isochromosomes. These abnormalities disrupt multiple genes in the affected regions, often leading to dysfunction of multiple organs and neurodevelopmental and epileptic disorders. For example, Down syndrome, caused predominantly by trisomy 21, is the most common cause of intellectual disability, with up to 13% of affected children experiencing epileptic seizures. Since deleted chromosomal regions typically include multiple genes, the contribution of individual genes to the phenotype is not always clear.

CNV, such as deletions and duplications, alter the dosage of genomic segments and are established risk factors for various types of epilepsy. High‐resolution CNV screening has become routine in clinical molecular diagnostics, resulting in a greater detection of chromosomal abnormalities. Causative CNV are identified in up to 4 % of people with epilepsy and more than 10 % of those with DEE.^9–12 Additional pathogenic CNV, which contribute to but do not entirely explain the phenotype, are found in an additional 4 % of cases.⁹ Most pathogenic and likely pathogenic CNV exceed one megabase (Mb) in size, and it is often unclear which gene(s) or genomic element(s) contribute to the phenotype.¹³ Mosaic pathogenic CNV are increasingly identified, with salivary DNA providing greater detection sensitivity than blood‐derived DNA because salivary epithelial cells are embryologically closer to neural cells.¹⁴

Chromosomal microarray is the standard test for detecting CNV of 1 kilobase or more. However, chromosomal microarray cannot detect balanced rearrangements, such as inversions, translocations and ring chromosomes. For example, karyotyping should be used when ring chromosome 20 syndrome is suspected. In ring chromosome 20 syndrome, the ends of the chromosome fuse to form a ring structure, often in a mosaic pattern, replacing the normal chromosome.¹⁵