PuSH - Publication Server of Helmholtz Zentrum München: Identification of intronic variants in <em>NDUFA3</em> as a cause of leigh syndrome by whole genome sequencing and RNA sequencing.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

Nakamura, K.* ; Kishita, Y.* ; Sugiura, A.* ; Ozaki, K.* ; Yatsuka, Y.* ; Matsumoto, N.* ; Okazaki, A.* ; Prokisch, H. ; Maruyama, K.* ; Iwasa, H.* ; Murayama, K.* ; Matsumoto, H.* ; Ohtake, A.* ; Shiraishi, Y.* ; Okazaki, Y.*

Identification of intronic variants in NDUFA3 as a cause of leigh syndrome by whole genome sequencing and RNA sequencing.

Neurol. Genet. 12:e200330 (2026)

Publ. Version/Full Text

Research data

DOI

PMC

	Open Access Gold

Abstract
Metrics
Extra information

Background and ObjectivesLeigh syndrome is an important manifestation of childhood-onset primary mitochondrial disease. Panel sequencing and whole exome sequencing are cost-effective for diagnosing mitochondrial diseases; however, more than half of mitochondrial disease cases remain genetically undiagnosed. This study aimed to demonstrate that combining whole genome sequencing (WGS) and RNA sequencing (RNA-seq) analyses can identify disease-causing variants that would otherwise be missed.MethodsWe performed WGS and RNA-seq on a patient with Leigh syndrome. Chromosomal phasing using Sanger sequencing of parental and patient blood samples was conducted to confirm compound heterozygous variants. RNA-seq data were analyzed for splicing abnormalities. Overexpression studies of wild-type NDUFA3 in patient-derived fibroblasts were performed to assess restoration of mitochondrial function.ResultsWe discovered compound heterozygous intronic variants (c.86-16_86-15del in intron2 and c.164-362G>A in intron3) of the NDUFA3 gene. RNA-seq data analysis revealed intron retention and exonization in NDUFA3. Exonization was related to a variant involving the mobile element Alu that resulted in complex abnormal splicing events. Overexpression of wild-type NDUFA3 restored mitochondrial dysfunction in patient-derived fibroblasts, confirming NDUFA3 as a Leigh syndrome causative gene.DiscussionThis study highlights the importance of combining WGS and RNA-seq and provides new insights into detecting abnormalities in deep intronic regions, particularly those involving mobile elements, such as Alu. This approach can play a crucial role in identifying genetic variations and elucidating transcriptional control mechanisms that are not readily achieved by conventional methods, especially in the context of mobile element-induced complexities.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Keywords Whole Genome Sequencing ; Identification (biology) ; Dna Sequencing ; Genome ; Intron ; Rna

ISSN (print) / ISBN 2376-7839

e-ISSN 2376-7839

Journal Neurology Genetics

Quellenangaben Volume: 12, Issue: 1, Article Number: e200330

Publisher American Academy of Neurology

Publishing Place Minneapolis, Minn.

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)