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Am. J. Hum. Genet., Oct 03 2023, S0002-9297(23)00321-X | https://doi.org/10.1016/j.ajhg.2023.09.008
Contribution and therapeutic implications of retroelement insertions in ataxia telangiectasia.
Boxun Zhao 1,2,3,4,5, Minh A. Nguyen 1, Sijae Woo 6, Jinkuk Kim 6, Timothy W. Yu 1,2,3,4,5, Eunjung Alice Lee 1,2,3,4,5
1Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA
2Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA
3Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Harvard Medical School, Boston, MA, USA
6Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
Corresponding authors: Timothy W. Yu, Eunjung Alice Lee
Abstract
Certain classes of genetic variation still escape detection in clinical sequencing analysis. One such class is retroelement insertion, which has been reported as a cause of Mendelian diseases and may offer unique therapeutic implications. Here, we conducted retroelement profiling on whole-genome sequencing data from a cohort of 237 individuals with ataxia telangiectasia (A-T). We found 15 individuals carrying retroelement insertions in ATM, all but one of which integrated in noncoding regions. Systematic functional characterization via RNA sequencing, RT-PCR, and/or minigene splicing assays showed that 12 out of 14 intronic insertions led or contributed to ATM loss of function by exon skipping or activating cryptic splice sites. We also present proof-of-concept antisense oligonucleotides that suppress cryptic exonization caused by a deep intronic retroelement insertion. These results provide an initial systematic estimate of the contribution of retroelements to the genetic architecture of recessive Mendelian disorders as ∼2.1%-5.5%. Our study highlights the importance of retroelement insertions as causal variants and therapeutic targets in genetic diseases.
논문정보
- Short communication
- 2023년 10월 (BRIC 등록일 2023-10-13)
- 국내+국외 연구진
- 의약학 > 유전 및 유전체의학
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