De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy

Epilepsy Genetics Initiative

doi:10.1038/gim.2017.100

Abstract

PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A—an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made.

Highlights

The Epilepsy Genetics Initiative (EGI) is a signature program of Citizens United for Research in Epilepsy
In 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A—an exon only recently added to the Consensus Coding Sequence database
One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort

Summary

Introduction

The Epilepsy Genetics Initiative (EGI) is a signature program of Citizens United for Research in Epilepsy (http://www. cureepilepsy.org/egi/index.html). The EGI reanalyzes data within the repository every 6 months with two broad goals: (i) to identify novel epilepsy genes through aggregate analyses of one of the largest sources of exome sequence data in patients with epilepsy and (ii) to reanalyze exome sequence data, using the most up-to-date knowledge, for missed genetic diagnoses in epilepsy patients who initially received an inconclusive result. Through the work of the EGI, we report here the identification of three novel disease-causing variants in alternative exon 5 A of SCN8A in three unrelated patients with epilepsy. These diagnoses were missed by clinical exome sequencing because, at the time of analysis, exon 5 A was not recognized as protein coding in the consensus coding sequence database (CCDS; https://www.ncbi.nlm.nih.gov/projects/CCDS/)

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Conclusion