Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome

Kiyoshi Yamaguchi, Rika Kasajima, Kiyoko Takane, Seira Hatakeyama, Eigo Shimizu, Rui Yamaguchi, Kotoe Katayama, Masami Arai, Chikashi Ishioka, Takeo Iwama, Satoshi Kaneko, Nagahide Matsubara, Yoshihiro Moriya, Tadashi Nomizu, Kokichi Sugano, Kazuo Tamura, Naohiro Tomita, Teruhiko Yoshida, Kenichi Sugihara, Yusuke NakamuraSatoru Miyano, Seiya Imoto, Yoichi Furukawa, Tsuneo Ikenoue

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

Original languageEnglish
Pages (from-to)1053-1060
Number of pages8
JournalJournal of Human Genetics
Issue number11
Publication statusPublished - 2021 Nov
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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