Genetic Testing Helped Find Causes In Some Epilepsies

What was studied

This study built a real-world database of 167 people with epilepsy and examined how often genetic testing identified a diagnosis. The researchers divided people into two groups: those with a genetic diagnosis and those without one, and compared clinical features between the groups.

They reported 66 patients with 44 different monogenic epilepsies. They also assessed the usefulness of clinical exome sequencing and biochemical investigations. For genetic changes that were not clearly disease-causing, they used computer-based 3D protein modeling to examine whether the changes were predicted to affect protein structure.

What they found

Clinical exome sequencing had a diagnostic yield of 31%. People with a genetic diagnosis more commonly had developmental delay, developmental brain malformation, movement disorder, and epilepsy starting before age 2. Biochemical investigations had a diagnostic yield of 0% in this study.

The researchers reported 19 genes of uncertain significance and described predicted protein structure changes in variants from these genes. Using these computer predictions, functional characterization of a LARP7 variant, and previous case series of genes of uncertain significance, they estimated that the exome sequencing yield could be 48% if some uncertain genes and variants are later shown to cause genetic epilepsies. They noted that these uncertain findings still require further functional characterization.

Limits of the evidence

This was mainly a database and observational study, so it cannot show that the uncertain gene changes actually caused epilepsy. The higher estimated diagnostic yield was not based on confirmed diagnoses for all of those genes; it was an estimate using computer modeling, one functionally characterized LARP7 variant, and prior case series.

The abstract does not give full details about ages, where patients were recruited, or how representative they were, so the results may not apply to every epilepsy clinic. Computer 3D protein modeling can suggest possible structural effects of a variant, but the abstract states that further functional characterization is still needed.

For families and caregivers

For families, this study suggests that genetic testing can identify a diagnosis in some people with epilepsy, especially when seizures start very early or occur along with developmental or movement-related features. It also shows that many families may still receive uncertain results rather than a clear genetic answer.

The study suggests that some currently uncertain gene findings may become clearer over time as more patients are studied and more laboratory work is done. However, these uncertain genes and variants should not yet be considered confirmed causes based on this study alone.

What to watch next

Further functional studies and international collaborations to better understand whether these uncertain genes and variants are involved in rare epilepsies.

Terms in this summary

monogenic

Related to a condition linked to a change in a single gene.

clinical exome sequencing

A genetic test that looks at many genes by reading the protein-coding parts of DNA.

diagnostic yield

The percentage of tests that provide a diagnosis.

variant of uncertain significance

A DNA change that is found, but it is not yet known whether it causes disease.

pathogenicity

How likely a genetic change is to cause disease.

in silico

Done by computer analysis rather than in a lab or in people.

phenotype

The signs and symptoms a person has.

genotype

A person's genetic makeup or specific gene changes.