Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing

Abstract

BackgroundWe intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate.MethodsWe assessed 74 patients with EOE whose seizures started before 3 years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software. Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Each case was further discussed in a monthly consensus meeting that included the participation of all laboratory personnel, bioinformaticians, geneticists, and clinicians.ResultsThe NGS panel identified 28 patients (37.8%) with genetic abnormalities; 25 patients had pathogenic or likely pathogenic SNVs in 17 genes including SXTBP1 (n = 3), CDKL5 (n = 2), KCNQ2 (n = 2), SCN1A (n = 2), SYNGAP1 (n = 2), GNAO1 (n = 2), KCNT1 (n = 2), BRAT1, WWOX, ZEB2, CHD2, PRICKLE2, COL4A1, DNM1, SCN8A, MECP2, SLC9A6 (n = 1). The other 3 patients had pathogenic CNVs (2 duplications and 1 deletion) with varying sizes (from 2.5 Mb to 12 Mb). The overall diagnostic yield was 37.8% after following our step-by-step approach for clinical consensus.ConclusionsNGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0320-7) contains supplementary material, which is available to authorized users.

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

“…It was recognized in 2016 that some GNAO1 mutations result in movement disorders without epilepsy (Kulkarni et al, 2016;Saitsu et al, 2016). To date there are over 70 published cases of children with mutations in GNAO1 presenting with early infantile epileptic encephalopathy (EIEE17: OMIM 615473) and/or neurodevelopmental disorder with involuntary movements (NEDIM: OMIM 617493) (Nakamura et al, 2013;Consortium et al, 2014;Law et al, 2015;Talvik et al, 2015;Ananth et al, 2016;Consortium, 2016;Dhamija et al, 2016;Gawlinski et al, 2016;Kulkarni et al, 2016;Marcé-Grau et al, 2016;Menke et al, 2016;Saitsu et al, 2016;Sanem et al, 2016;Arya et al, 2017;Danti et al, 2017;Sakamoto et al, 2017;Schorling et al, 2017;Blumkin et al, 2018;Bruun, 2018;Gerald et al, 2018;Honey et al, 2018;Koy et al, 2018;Marecos et al, 2018;Okumura et al, 2018;Rim et al, 2018;Schirinzi et al, 2018;Takezawa et al, 2018;Waak et al, 2018;Xiong et al, 2018;Meredith et al, 2019). This article has not been copyedited and formatted.…”

Diagnostic Yield of Epilepsy Panel Testing in Patients With Seizure Onset Within the First Year of Life

“…To date, many studies have reported on the clinical utility of epilepsy gene panel testing. Although many custom-designed epilepsy gene panels produce similar lists of genes with pathogenic variants, there is substantial variability in their diagnostic rates, which range from 10 to 50% (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). This suggests that the diagnostic yield in these studies depends more on which patients are selected than on which custom-designed panel is used.…”

Peer Review #3 of "Genetic characteristics of non-familial epilepsy (v0.1)"

“…Insofar as non-familial focal epilepsy only and non-familial adulthood-onset epilepsy only were concerned, the diagnostic yields were 14.6% (31/213) and 14.7% (16/109), respectively. Although other study designs varied such that direct comparison to our study may not be suitable, there was a distinct tendency of higher genetic yields to associate with early childhood epilepsy with a distinct phenotype such as early onset DEEs, a positive history of familial epilepsy, or a generalized epilepsy (Lemke et al, 2012;Carvill et al, 2013;Kodera et al, 2013;Wang et al, 2014;Della Mina et al, 2015;Mercimek-Mahmutoglu et al, 2015;Hildebrand et al, 2016;Møller et al, 2016;Dunn et al, 2018;Ko et al, 2018;Rim et al, 2018;Lee et al, 2018). Given that the present study examined primarily non-familial focal PeerJ reviewing PDF | (2019:06:38371:1:2:NEW 4 Oct 2019)…”

“…The higher diagnostic yield of genetic testing in DEEs has been associated with primarily drug-refractory seizures (Møller et al, 2016;Ko et al, 2018;Rim et al, 2018), which indicates that causal genes of DEEs could be linked to pharmacoresistance. Indeed, the target hypothesis is PeerJ reviewing PDF | (2019:06:38371:1:2:NEW 4 Oct 2019)…”