A team of researchers at Children’s Hospital of Philadelphia (CHOP) affiliated with the CHOP Epilepsy Neurogenetics Initiative (ENGIN) have combined clinical information with large-scale genomic data to successfully link characteristic presentations of childhood epilepsies with specific genetic variants. The findings were published today in the American Journal of Human Genetics.

Developmental and Epileptic Encephalopathies (DEE), a group of severe brain disorders that can cause difficult-to-treat seizures, cognitive and neurological impairment, and, in some cases, early death, are known to have more than 100 underlying genetic causes. However, matching characteristic clinical features and outcomes with specific genetic mutations can be especially daunting given the large number of genetic causes, each of which is very rare.

When genetic information is collected, a person’s phenotype—or clinical features—are typically also documented. However, while genetic information is collected in a standardized manner, the same is not true when describing clinical symptoms, which makes it difficult when trying to pinpoint whether certain genetic mutations are responsible for specific clinical features.

Building upon their previous work, researchers from CHOP utilized the Human Phenotype Ontology (HPO), which provides a standardized format to characterize a patient’s phenotypic features and allows clinical data to be used at a similar level as genetic data.

“For this study, we used phenotypic and genetic information that had been collected in several important cohorts for more than a decade,” said Ingo Helbig, MD, attending physician at ENGIN, director of the genomic and data science core of ENGIN and lead investigator of the study. “In this study alone, we found associations of 11 genetic causes with specific phenotypes. Without methods to systematically analyze clinical data, we could not have possibly done this previously, even with this robust cohort of patients.”

In total, the study team analyzed 31,742 HPO terms in 846 patients with existing whole exome sequencing data. Some examples of causative genes in DEE identified in this study were SCN1A, which was associated with complex febrile seizures and focal clonic seizures; STXBP1, which was associated with absent speech; and SLC6A1, which was associated with EEG with generalized slow activity. In total, 41 genes with variants presented in at least two individuals, and 11 of those genes showed significant similarity between phenotypes of the patients with changes in these genes. Using a statistical analysis, the researchers showed that this was more than would be possible via chance.

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