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Intronic LINE-1 insertion in SLCO1B3 as a highly prevalent cause of rotor syndrome in East Asian population

Journal of Human Genetics volume 67, pages 71–77 (2022)Cite this article

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Abstract

Rotor syndrome is caused by digenic loss-of-function variants in SLCO1B1 and SLCO1B3 but only a few studies have reported co-occurring inactivating variants from both genes. A rotor syndrome-causing long interspersed element-1 (LINE-1) insertion in SLCO1B3 had been reported to be highly prevalent in the Japanese population but there has been no additional report. In spite of its known association with various human diseases, LINE-1 is hard to detect with current sequencing technologies. In this study, we aimed to devise a method to screen the LINE-1 insertion variant and investigate the frequency of this variant in various populations. A chimeric sequence, that was generated by concatenating the reference sequence at the junction and a part of inserted LINE-1 sequence, was searched from 725 raw sequencing data files. In cases containing the chimeric sequence, confirmatory long-range PCR and gap-PCR were performed. In total, 95 (13.1%) of 725 patients were positive for the chimeric sequence, and all were confirmed to have the SLCO1B3 LINE-1 insertion by PCR-based tests. The same chimeric sequence was searched from the 1000 Genomes Project data repository and the carrier frequency was remarkably high in the East Asian populations (10.1%), especially in Southern Han Chinese (18.5%), but almost absent in other populations. This SLCO1B3 LINE-1 insertion should be screened in a population-specific manner under suspicion of Rotor syndrome and the methods proposed in this study would enable this in a simple way.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Young-gon Kim, Hobin Sung, Ho Seob Shin, Man Jin Kim, Jee-Soo Lee, Sung-Sup Park & Moon-Woo Seong

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Correspondence to Moon-Woo Seong.

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Supplementary information

10038_2021_967_MOESM1_ESM.xlsx

Supplemental Table S1. List of individuals and files included from 1000 Genomes Project (File access : ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data, last accessed 10 June, 2021)

Supplementary Table S2. Primers used for amplification and sequencing

10038_2021_967_MOESM3_ESM.xlsx

Supplementary Table S3. BAM file findings and confirmatory PCR results for the detecion of intronic LINE-1 insertion in SLCO1B3 (95 positive cases from SNUH repository data)

Supplementary Table S4. VAF estimation of chimeric sequence-positive samples from 1000 Genomes Project

10038_2021_967_MOESM5_ESM.xlsx

Supplementary Table S5. SLCO1B1 c.1738C>T, p.R580* variant positive individuals in 1000 Genomes Project and their predicted status of SLCO1B3 LINE-1 insertion revealed in this study

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Kim, Yg., Sung, H., Shin, H.S. et al. Intronic LINE-1 insertion in SLCO1B3 as a highly prevalent cause of rotor syndrome in East Asian population. J Hum Genet 67, 71–77 (2022). https://doi.org/10.1038/s10038-021-00967-1

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