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Determining the best candidates for next-generation sequencing-based gene panel for evaluation of early-onset epilepsy.

ABSTRACT: BACKGROUND:Genetic testing is an emerging diagnostic approach in early-onset epilepsy. Identification of the heterogeneous genetic causes of epilepsy may mitigate unnecessary evaluations and allow more accurate diagnosis and therapy. We aimed to uncover genetic causes of early-onset epilepsy using next-generation sequencing (NGS) to elucidate the diagnostic candidates and evaluate the diagnostic yield of targeted gene panel testing. METHODS:We evaluated 116 patients with early-onset epilepsy developed before 2 years old and normal brain imaging using a NGS-based targeted gene panel. Variants were classified according to their pathogenicity, and the diagnostic yield of the targeted genes and associated clinical factors were determined. RESULTS:We detected 40 disease-causing variants with diagnostic yield of 34.5% (19 pathogenic, 21 likely pathogenic). Twelve variants were novel. The most commonly detected genes were SCN1A, associated with Dravet syndrome, and PRRT2, associated with benign familial infantile epilepsy. Other variants were identified in ARX, SCN2A, KCNQ2, PCDH19, STXBP1, DEPDC5, and SCN8A. The age of seizure onset and family history were associated with disease-causing variants. CONCLUSION:Next-generation sequencing-based targeted testing is an effective diagnostic test, with 30%-40% comparable diagnostic yield. Patients with earlier seizure onset and family history of epilepsy were the best candidates for testing. For pediatric patients with early-onset epilepsy, genetic diagnosis is important for accurate prognosis and treatment.

SUBMITTER: Lee J

PROVIDER: S-EPMC7507365 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Determining the best candidates for next-generation sequencing-based gene panel for evaluation of early-onset epilepsy.

Lee Jiwon J Lee Chung C Ki Chang-Seok CS Lee Jeehun J

Molecular genetics & genomic medicine 20200701 9

<h4>Background</h4>Genetic testing is an emerging diagnostic approach in early-onset epilepsy. Identification of the heterogeneous genetic causes of epilepsy may mitigate unnecessary evaluations and allow more accurate diagnosis and therapy. We aimed to uncover genetic causes of early-onset epilepsy using next-generation sequencing (NGS) to elucidate the diagnostic candidates and evaluate the diagnostic yield of targeted gene panel testing.<h4>Methods</h4>We evaluated 116 patients with early-ons ...[more]

PMID: 32613771

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Project description:PurposeThe demand for high-throughput genetic profiling of somatic mutations in cancer tissues is growing. We sought to establish a targeted next generation sequencing (NGS) panel test for clinical oncology practice.MethodsCustomized probes were designed to capture exonic regions of 141 genes selected for the panel, which was aimed for the detection of clinically actionable genetic variations in cancer, including KRAS, NRAS, BRAF, ALK, ROS1, KIT and EGFR. The size of entire targeted regions is 0.8 Mb. Library preparation used NEBNext Ultra II FS kit coupled with target enrichment. Paired-end sequencing was run on Illumina NextSeq 500 at a read length of 150 nt. A bioinformatics workflow focusing on single nucleotide variant and short insertions and deletions (SNV/indel) discovery was established using open source, in-house and commercial software tools. Standard reference DNA samples were used in testing the sensitivity and precision and limit of detection in variant calling.ResultsThe general performance of the panel was observed in pilot runs. Average total reads per sample ranged from 30 million to 48 million, 73% ~82% unique reads. All runs had more than 99% average mapping rate. Mean target coverage ranged from 727x to 879x. Depth of coverage at 50x or more reached 87% of targeted region and 60% of targeted region received 500x or more coverage depth. Using OncoSpan HD827 DNA, which bears 144 variants (SNV/indel) from 80 genes that are within the targeted region on the panel, our somatic variant calling pipeline reached 97% sensitivity and 100% precision respectively, with near 48 million reads. High concordance with orthogonal approaches in variant detection was further verified with 7 cancer cell lines and 45 clinical specimens.ConclusionWe developed a NGS panel with a focus on clinically actionable gene mutations and validated the performance in library construction, sequencing and variant calling. High concordance with reference materials and orthogonal mutation detection was observed.

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Determining the best candidates for next-generation sequencing-based gene panel for evaluation of early-onset epilepsy.

Publications

Determining the best candidates for next-generation sequencing-based gene panel for evaluation of early-onset epilepsy.

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