[BO] Oral Presentation Award Session

[BO-4] Alu-mediated genomic rearrangements revealed by multi-omics analysis

^○Yoshihito Kishita^1,2,4, Kazuhiro R Nitta², Yukiko Yatsuka², Atsuko Okazaki², Ayumu Sugiura², Takuya Fushimi³, Nanako Omichi⁴, Akira Ohtake^5,6, Kei Murayama^3,7, Yasushi Okazaki^2,8 (1.epartment of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan, 2.Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan, 3.Department of Metabolism, Chiba Children's Hospital, Chiba, Japan, 4.Kindai University, Graduate School of Science and Engineering, Genetic Counselor Training Course, Osaka, Japan, 5.Department of Pediatrics & Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, Japan, 6.Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan, 7.Center for Medical Genetics, Chiba Children's Hospital, Chiba, Japan, 8.Laboratory for Comprehensive Genomic Analysis, RIKEN Centre for Integrative Medical Sciences, Kanagawa, Japan)

[Objective] Mitochondrial disease is the most common inborn errors of metabolism that present with abnormal mitochondrial function. This disease can be caused by both mitochondrial and nuclear-encoded genes. Although conventional panel sequencing and whole exome sequencing are effective for diagnosis, a certain number of cases remain unresolved in practice. Therefore, it is necessary to investigate the cause of the disease from a multifaceted approach. In this study, we aimed to elucidate the cause of undiagnosed cases by combining whole genome sequencing, RNA sequencing and proteome analysis. [Methods] We searched for causative variants by whole genome sequencing, RNA sequencing, and proteome analysis, focusing on cases that had not been diagnosed by panel sequencing or whole exome sequencing. In cases that we found candidate causative variants, we performed PCR and Sanger sequencing of family members to elucidate the genetic form. [Results and discussion] We found candidate causative genes with abnormal gene expression by multi-omics analysis. The whole genome sequencing identified deletions of several kilobases in causative genes, including NDUFV2, NFU1, and others. Detailed examination of the deletion sites revealed that the deletions were mediated by Alu element, suggesting that recombination between different Alu element caused the deletions, and that the deletions were accompanied by Alu mediated insertion. It is expected that such Alu-mediated structural variations will be found as the number of analyses by whole genome sequencing increases.