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.

“It’s a bespoke system we developed ourselves,” first study author Norman Delanty, MD, said in an interview. The genetics of epilepsy and other neurologic diseases is “an evolving story,” said Dr. Delanty, associate professor at Royal College of Surgeons in Ireland (RCSI) and consultant neurologist at Beaumont Hospital, both in Dublin, and investigator at FutureNeuro. “I don’t think a lot of health care systems are ready for this.” While the integration of exome-sequencing results into EHRs has the potential to facilitate precision medicine, “old-fashioned medicine remains para-mount,” Dr. Delanty said. New tools do not supplant the need for a comprehensive history, for example. “The fundamentals of clinical medicine are never going to change,” he said. The exome – the protein-coding region of the genome – has proven important in understanding the causes of unexplained diseases. Of the 50-60 million people with epilepsy, about 40% do not have a clear clinical cause. Increasingly, researchers are finding pathogenic variants in the genome, Dr. Delanty said. 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.” Dr. Norman Delanty

The Irish National Epilepsy Electronic Patient Record (EPR) is used at tertiary centers across Ireland. It contains data from more than 8,000 patients regarding demographics, epilepsy history, current and prior antiepileptic drugs, allergies, comorbidities, epilepsy surgery, vagus nerve stimulation, nurse telephone ad-vice line interactions, and care plans. The researchers’ involvement in multicenter collaborative clinical genetic research prompted them to develop the genomic medicine module. “To our knowledge, the epilepsy genomics module we have developed is the first such specific system in the world. We believe the combined power of genomics and electronic patient records has the capability of enhancing, and in some cases transforming, the practice of medicine,” study coauthor Mary Fitzsimons, FutureNeuro epilepsy e-health lead and director of the Epilepsy Lighthouse Project at RCSI, said in a news release. “Diagnostic genomic testing is a rapidly growing area in clinical medicine, but there is much work to be done to understand the most effective way to integrate this powerful information into patient care. We hope this new e-health technology can inform how genomics is integrated into the Irish healthcare system and act as an example for other diseases beyond epilepsy,” Gianpiero Cavalleri, PhD, FutureNeuro deputy director and professor of Human Genetics at RCSI, said in the release.

Dr. Gianpiero Cavalleri

The genomics module in action Before a multidisciplinary epilepsy genomics review meeting, users can “Upload Genomic Case File,” “Upload Patient Pedigree,” and enter “Additional Phenotype” information. During the meeting, selecting “Patient Case” loads the patient’s phenotype, family pedigree, clinical photography, genomic data, and action plan. The phenotype interface presents a summary of clinical epileptology information from different areas of the electronic patient record. The family pedigree, based on information gathered by a clinical researcher or research nurse during family interviews, is included as a PDF. Photographs taken by a clinical geneticist to document dysmorphic features also are available. The genomic data section presents findings from whole exome sequencing and copy number variant analysis. “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 Med-ical 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 (www.cureepilepsy.org), 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.

Genome-wide significant loci of all analyses and prioritized biological epilepsy genes. Genes were prioritized based on 6 criteria and scored based on the number of criteria met per gene (filled red boxes). Credit: ILAE Consortium on Complex Epilepsies. Nat Commun. 2018;9(1):5269. doi: 10.1038/s41467-018-07524-z./ CC BY 4.0

Ruth Ottman, PhD, commentary: System brings key information together Epilepsy genetics (and clinical care) is complicated because of the extreme heterogeneity of the disorders, in terms of clinical presentation, the genetic mechanisms involved, and the relationships between clinical features and genetics. Recording the clinical information in a standardized way is challenging by itself, and adding the genomics is even more challenging – so the system Delanty and colleagues describe sounds like an excellent way to bring all of the needed in-formation together and make it accessible to a multidisciplinary team involved in patient care. I suspect this type of system is extremely rare, if not unique. Given the very strong emphasis on genomic research in epilepsy now (with major international collaborations involved in sequencing on a large scale), I don’t think it is too early to be developing this kind of approach. For some types of epilepsy – particularly the severe, early-childhood epilepsies associated with intellectual disability – genomic findings are common (24% in a recent population-based study ). However, among people with epilepsy without intellectual disability (comprising the vast majority), the proportion with a pathogenic genomic variant re-mains very low. So for most patients at this time, the excellent system for recording genomic information will not have any findings. Delanty et al. do not discuss what happens after a genomic finding is obtained. How are decisions made about changes in clinical management? How is the patient or family informed? Is there any monitoring of their response to receiving the information, and what kinds of support services are put into place? It would be extremely useful and important to build into the system some variables that record these aspects of patient care. Dr. Ottman is a professor of epidemiology and deputy director for research at the G.H. Sergievsky Center at Columbia University in New York.

Dr. Ruth Ottman