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

John Hoon Rim, Se Hee Kim, In Sik Hwang, Soon Sung Kwon, Jieun Kim, Hyun Woo Kim, Min Jung Cho, Ara Ko, Song Ee Youn, Jihun Kim, Young Mock Lee, Hee Jung Chung, Joon Soo Lee, HeungDong Kim, Jong Rak Choi, Seung Tae Lee, hoonchul kang

Research output: Contribution to journalArticle

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Abstract

Background: We 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. Methods: We 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. Results: The 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. Conclusions: NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.

Original languageEnglish
Article number6
JournalBMC Medical Genomics
Volume11
Issue number1
DOIs
Publication statusPublished - 2018 Feb 1

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Epilepsy
Genes
Nucleotides
Laboratory Personnel
Genomics
Seizures
Software
Guidelines

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Rim, John Hoon ; Kim, Se Hee ; Hwang, In Sik ; Kwon, Soon Sung ; Kim, Jieun ; Kim, Hyun Woo ; Cho, Min Jung ; Ko, Ara ; Youn, Song Ee ; Kim, Jihun ; Lee, Young Mock ; Chung, Hee Jung ; Lee, Joon Soo ; Kim, HeungDong ; Choi, Jong Rak ; Lee, Seung Tae ; kang, hoonchul. / Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. In: BMC Medical Genomics. 2018 ; Vol. 11, No. 1.
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abstract = "Background: We 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. Methods: We 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. Results: The 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. Conclusions: NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.",
author = "Rim, {John Hoon} and Kim, {Se Hee} and Hwang, {In Sik} and Kwon, {Soon Sung} and Jieun Kim and Kim, {Hyun Woo} and Cho, {Min Jung} and Ara Ko and Youn, {Song Ee} and Jihun Kim and Lee, {Young Mock} and Chung, {Hee Jung} and Lee, {Joon Soo} and HeungDong Kim and Choi, {Jong Rak} and Lee, {Seung Tae} and hoonchul kang",
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Rim, JH, Kim, SH, Hwang, IS, Kwon, SS, Kim, J, Kim, HW, Cho, MJ, Ko, A, Youn, SE, Kim, J, Lee, YM, Chung, HJ, Lee, JS, Kim, H, Choi, JR, Lee, ST & kang, H 2018, 'Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing', BMC Medical Genomics, vol. 11, no. 1, 6. https://doi.org/10.1186/s12920-018-0320-7

Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. / Rim, John Hoon; Kim, Se Hee; Hwang, In Sik; Kwon, Soon Sung; Kim, Jieun; Kim, Hyun Woo; Cho, Min Jung; Ko, Ara; Youn, Song Ee; Kim, Jihun; Lee, Young Mock; Chung, Hee Jung; Lee, Joon Soo; Kim, HeungDong; Choi, Jong Rak; Lee, Seung Tae; kang, hoonchul.

In: BMC Medical Genomics, Vol. 11, No. 1, 6, 01.02.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing

AU - Rim, John Hoon

AU - Kim, Se Hee

AU - Hwang, In Sik

AU - Kwon, Soon Sung

AU - Kim, Jieun

AU - Kim, Hyun Woo

AU - Cho, Min Jung

AU - Ko, Ara

AU - Youn, Song Ee

AU - Kim, Jihun

AU - Lee, Young Mock

AU - Chung, Hee Jung

AU - Lee, Joon Soo

AU - Kim, HeungDong

AU - Choi, Jong Rak

AU - Lee, Seung Tae

AU - kang, hoonchul

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Background: We 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. Methods: We 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. Results: The 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. Conclusions: NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.

AB - Background: We 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. Methods: We 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. Results: The 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. Conclusions: NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.

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U2 - 10.1186/s12920-018-0320-7

DO - 10.1186/s12920-018-0320-7

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VL - 11

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