Methodology

Method: Next-generation sequencing with CNV calling (NGS-CNV)

Please note that while the EpiXpanded panel captures and sequences the whole exome, analysis is targeted to the specific phenotype-driven gene list for the EpiXpanded panel. The EpiXpanded Panel gene list includes more than 1300 genes. The list was developed by searching for genes associated with the phenotypes “Seizures”, “Epilepsy”, and “Epileptic Encephalopathy” in multiple sources, including OMIM, HGMD, and Human Phenotype Ontology (HPO) terms categorized within the “Seizure” branch. Additionally, genes were added to the list using GeneDx data from clinical whole exome sequencing done on patients with epilepsy and from emerging literature about new genes causing epilepsy. The gene list is systematically updated at least quarterly. 

Data are filtered and analyzed to identify sequence variants and most deletions and duplications involving three or more coding exons. Smaller deletions or duplications may not be reliably identified.

The average coverage of all genes on the panel is greater than 98% at 10X (with a depth of 10 or more reads). Several genes with a high clinical sensitivity have an average coverage of less than 90% coverage at 10X, including ARX, FOXG1, EPM2A, and SLC6A8. The coverage of each gene on the panel for a specific patient may vary, and the actual coverage for each gene is included in the final report.

Some types of genetic disorders, such as those due to nucleotide repeat expansion/contraction, abnormal DNA methylation, and other mechanisms may not be detectable with this test. Additionally, small sections of a few individual genes have inherent sequence properties that yield suboptimal data and mutations in those regions may not be reliably detected. Specifically, the CGG repeat expansions in FMR1 causing fragile X syndrome, the polyalanine repeat expansions in ARX, the common dodecamer repeat expansion in CSTB associated with Unverricht-Lundborg disease, and abnormal methylation of UBE3A causing Angelman syndrome would not be detectable by this EpiXpanded Panel.

Variants of uncertain significance, likely benign and benign variants, if present, are not routinely reported.