PT  - JOURNAL ARTICLE
AU  - Miller, Katherine E.
AU  - Koboldt, Daniel C.
AU  - Schieffer, Kathleen M.
AU  - Bedrosian, Tracy A.
AU  - Crist, Erin
AU  - Sheline, Adrienne
AU  - Leraas, Kristen
AU  - Magrini, Vincent
AU  - Zhong, Huachun
AU  - Brennan, Patrick
AU  - Bush, Jocelyn
AU  - Fitch, James
AU  - Bir, Natalie
AU  - Miller, Anthony R.
AU  - Cottrell, Catherine E.
AU  - Leonard, Jeffrey
AU  - Pindrik, Jonathan A.
AU  - Rusin, Jerome A.
AU  - Shah, Summit H.
AU  - White, Peter
AU  - Wilson, Richard K.
AU  - Mardis, Elaine R.
AU  - Pierson, Christopher R.
AU  - Ostendorf, Adam P.
TI  - Somatic <em>SLC35A2</em> mosaicism correlates with clinical findings in epilepsy brain tissue
AID  - 10.1212/NXG.0000000000000460
DP  - 2020 Aug 01
TA  - Neurology Genetics
PG  - e460
VI  - 6
IP  - 4
4099  - http://ng.neurology.org/content/6/4/e460.short
4100  - http://ng.neurology.org/content/6/4/e460.full
SO  - Neurol Genet2020 Aug 01; 6
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