The Epilepsy Genetics Initiative – novel diagnoses through exome re-analysis

The negative exome. Despite writing a lot about the power of next generation sequencing technologies to provide a genetic diagnosis in individuals with severe epilepsies, it is important to remember that most exome tests performed in a diagnostic setting are negative. Even the most optimistic studies do not find a diagnostic yield that exceeds 40%. However, what can be done about the 60-70% of patients who had undergone exome sequencing, the current gold-standard diagnostic testing, but have received a negative test result? A systematic re-analysis after 12-24 months is currently considered one possibility to make sense of existing exome data. In a current publication, the Epilepsy Genetics Initiative (EGI) reports their results of a systematic research-based re-analysis in 166 individuals with epilepsy. In eight individuals, a novel diagnosis could be achieved, including novel genes not known at the time of the initial report and novel mechanisms such as alternative exons. With a diagnostic rate of 6%, this study provides a unique benchmark of what can be expected when exomes initially come back as negative. Continue reading

What’s new with SCN8A – a 2016 update

An unexpected twist in the SCN8A story. SCN8A mutations were first implicated in epilepsy in 2012, when a de novo missense variant was identified in a patient with early infantile epileptic encephalopathy (EIEE) via genome sequencing. Since then, a number of patients with de novo heterozygous SCN8A variants and epilepsy have been reported, firmly establishing the role of SCN8A in EIEE, and we have learned a lot about the associated phenotype, mutation spectrum and disease mechanism within the last four years. Recently, a heterozygous familial SCN8A missense variant was identified in several families with a significantly milder epilepsy phenotype than reported in previous patients. Read further to learn more about the expanded SCN8A-associated epilepsy phenotype. Continue reading

SCN8A – this is what you need to know in 2015

SCN8A. In 2015, SCN8A has emerged as an important gene in epileptic encephalopathy. SCN8A encodes the voltage-gated sodium channel alpha subunit Nav1.6, and was first implicated in epileptic encephalopathy in 2012. Since then, approximately 100 cases of early-infantile epileptic encephalopathy caused by mutations of SCN8A have been identified, and the disorder has been designated EIEE13. Here is what you need to know about SCN8A in 2015.

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