Genomic data in the EHR? Bespoke system for patients with epilepsy probes the possibilities

Month by month, the literature on epilepsy genetics evolves.

To keep up, researchers in Ireland have created a custom genomics module for their electronic health record (EHR) for patients with epilepsy.

When epileptologists, epilepsy research nurses, bioinformaticians, and geneticists meet to discuss patients’ genetic test results, they use the genomics module to review candidate pathogenic gene variants in the context of a patient’s phenotype. “The discussions at the [multidisciplinary team meeting] are complex and require fast but secure access to the genetic and clinical data,” the researchers wrote in an article describing the module, which may be the first such system for patients with epilepsy.

Soon, the module may become part of the main clinical electronic patient record for patients with epilepsy in Ireland, the researchers said in the August 2019 issue of Epilepsia.

International collaborations have identified causative mutations and established a need to “curate the genomic data and reanalyze it over time,” he said. One recent study by the Epilepsy Genetics Initiative found that systematic reanalysis of 139 exomes led to eight new diagnoses.

The genomics module lists potential pathogenic variants. Patients may have three or four mutations on record. The mutations could be de novo or from the mother or father. “Of course, we don’t always find the cause. Many patients are unsolved,” Dr. Delanty said.

Early genetic testing may help patients “avoid a long diagnostic journey that may be fruitless,” he said. It also may help researchers study “the nascent potential of precision therapeutics,” Dr. Delanty and coauthors wrote in their description of the module’s development.

“The potential to understand at a molecular level the reason for a particular patient’s epilepsy and to use this information to inform on precision therapy will become a significant advance in the way we practice clinical epileptology,” they wrote. “… routine early diagnostic sequencing may soon accompany magnetic resonance imaging (MRI) and electroencephalography (EEG) as standard of care for many of our patients. … Many of our patients (both adults and children) with epilepsy of unknown etiology now undergo genomic sequencing, especially if there is a family history or significant comorbidity such as intellectual disability.”

“A custom, in‐house bioinformatics pipeline incorporating Genome Analysis Toolkit best practices and Annotate Variation is used for analysis of the sequencing data,” the authors wrote. Researchers identify rare, functional, and predicted damaging sequence variants, as well as those associated with epilepsy or intellectual disability. “The final list of ‘qualifying variants’ for each patient is then stratified according to pathogenicity using the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology guidelines. Those categorized, on the basis of current evidence, as a variant of unknown significance (VUS), likely pathogenic variant, or pathogenic variant are then uploaded onto the genomics module … and brought forward for further discussion at the multidisciplinary epilepsy genomics review meeting,” they said. “In parallel, potentially pathogenic copy number variants that pass quality control thresholds of the array are stratified using the appropriate ACMG guidelines, and included for discussion at the epilepsy genomics review meeting.”

In addition, participants document follow‐up plans, such as meetings between the clinical geneticist and the patient and family, and accreditation of putative causative variants in an accredited laboratory.

“A patient case may be decided as being completed (‘closed’) or may be listed for further discussion at a future [meeting]. Patients with a variant of unknown significance are invited to enroll in the Epilepsy Genetics Initiative, a multicenter study that prospectively and regularly (every 6 months) interrogates participant exome data to determine novel causative variants on the basis of new and evolving knowledge,” the authors explained.

After the meeting, minutes are available to authorized EHR users, including clinicians who care for the patient. Data also are available for researchers in a format that removes patient identifiers.

“Although EPRs are being used in a number of complex epilepsy centers, it is difficult to ascertain how many epilepsy‐specific or epilepsy‐oriented EPRs are in use around the world. Furthermore, the level of deep phenotypic detail is likely to vary from system to system, and no firm guidelines have been issued by organizations such as the ILAE [International League Against Epilepsy] on the use and quality of epilepsy EPRs. We are not aware of any other center using a bespoke genomics module within an epilepsy EPR to facilitate research, education, and clinical practice in epilepsy genomics. To our knowledge, the epilepsy genomics module presented here is the first such specific system described in the literature.”

The research was funded by eHealth Ireland, the Health Service Executive, and Science Foundation Ireland.