Genome sequencing and RNA-seq analyses of mitochondrial complex I deficiency revealed Alu insertion-mediated deletion in NDUFV2

Yoshihito Kishita; Masaru Shimura; Masakazu Kohda; Takuya Fushimi; Kazuhiro R Nitta; Yukiko Yatsuka; Shinichi Hirose; Hiroshi Ideguchi; Akira Ohtake; Kei Murayama; Yasushi Okazaki

doi:10.1002/humu.24274

Genome sequencing and RNA-seq analyses of mitochondrial complex I deficiency revealed Alu insertion-mediated deletion in NDUFV2

Hum Mutat. 2021 Nov;42(11):1422-1428. doi: 10.1002/humu.24274. Epub 2021 Sep 2.

Authors

Yoshihito Kishita^{1

2}, Masaru Shimura³, Masakazu Kohda¹, Takuya Fushimi³, Kazuhiro R Nitta¹, Yukiko Yatsuka¹, Shinichi Hirose⁴, Hiroshi Ideguchi⁵, Akira Ohtake^{6

7}, Kei Murayama^{1

3

8}, Yasushi Okazaki^{1

9}

Affiliations

¹ Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
² Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan.
³ Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
⁴ General Medical Research Center, School of Medicine, Fukuoka University, Fukuoka, Japan.
⁵ Department of Pediatrics, Fukuoka Sanno Hospital, Fukuoka, Japan.
⁶ Department of Pediatrics & Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
⁷ Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
⁸ Center for Medical Genetics, Chiba Children's Hospital, Chiba, Japan.
⁹ Laboratory for Comprehensive Genomic Analysis, RIKEN Centre for Integrative Medical Sciences, Kanagawa, Japan.

PMID: 34405929
DOI: 10.1002/humu.24274

Abstract

Isolated complex I deficiency is the most common cause of pediatric mitochondrial disease. Exome sequencing (ES) has revealed many complex I causative genes. However, there are limitations associated with identifying causative genes by ES analysis. In this study, we performed multiomics analysis to reveal the causal variants. We here report two cases with mitochondrial complex I deficiency. In both cases, ES identified a novel c.580G>A (p.Glu194Lys) variant in NDUFV2. One case additionally harbored c.427C>T (p.Arg143*), but no other variants were observed in the other case. RNA sequencing showed aberrant exon splicing of NDUFV2 in the unsolved case. Genome sequencing revealed a novel heterozygous deletion in NDUFV2, which included one exon and resulted in exon skipping. Detailed examination of the breakpoint revealed that an Alu insertion-mediated rearrangement caused the deletion. Our report reveals that combined use of transcriptome sequencing and GS was effective for diagnosing cases that were unresolved by ES.

Keywords: Alu element; RNA-seq; genome sequencing; mitochondrial complex I; mitochondrial disorder.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Alu Elements*
Electron Transport Complex I / deficiency*
Electron Transport Complex I / genetics
Female
Gene Deletion*
Genome, Human*
Humans
INDEL Mutation*
Infant
Male
Mitochondrial Diseases / diagnosis
Mitochondrial Diseases / genetics*
NADH Dehydrogenase / genetics*
Pedigree
Sequence Analysis, RNA / methods*

Substances

NADH Dehydrogenase
Electron Transport Complex I
NDUFV2 protein, human

Supplementary concepts

Mitochondrial complex I deficiency