RT Journal Article
SR Electronic
T1 Somatic <em>SLC35A2</em> mosaicism correlates with clinical findings in epilepsy brain tissue
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams &amp; Wilkins
SP e460
DO 10.1212/NXG.0000000000000460
VO 6
IS 4
A1 Miller, Katherine E.
A1 Koboldt, Daniel C.
A1 Schieffer, Kathleen M.
A1 Bedrosian, Tracy A.
A1 Crist, Erin
A1 Sheline, Adrienne
A1 Leraas, Kristen
A1 Magrini, Vincent
A1 Zhong, Huachun
A1 Brennan, Patrick
A1 Bush, Jocelyn
A1 Fitch, James
A1 Bir, Natalie
A1 Miller, Anthony R.
A1 Cottrell, Catherine E.
A1 Leonard, Jeffrey
A1 Pindrik, Jonathan A.
A1 Rusin, Jerome A.
A1 Shah, Summit H.
A1 White, Peter
A1 Wilson, Richard K.
A1 Mardis, Elaine R.
A1 Pierson, Christopher R.
A1 Ostendorf, Adam P.
YR 2020
UL http://ng.neurology.org/content/6/4/e460.abstract
AB Objective Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.Methods We have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.Results We used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in SLC35A2, present at a range of variant allele fractions (4.2%–19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the SLC35A2 variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.Conclusions Our findings support the importance of tissue-based sequencing and highlight a correlation in our patient between SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.ACMG=American College of Medical Genetics and Genomics; AMP=Association for Molecular Pathology; FCD=focal cortical dysplasia; FDG=fluorodeoxyglucose; FFPE=formalin-fixed paraffin embedded; FPKM=Fragments Per Kilobase of transcript per Million; IGV=Integrated Genomics Viewer; NGS=next-generation sequencing; NMD=nonsense-mediated decay; NND=NEBNext Direct; UMI=unique molecular identifier; VAF=variant allele fraction; VUS=variant of unknown significance