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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Whole Genome Sequencing ; Identification (biology) ; Dna Sequencing ; Genome ; Intron ; Rna
ISSN (print) / ISBN 2376-7839
e-ISSN 2376-7839
Zeitschrift Neurology Genetics
Quellenangaben Band: 12, Heft: 1, Seiten: , Artikelnummer: e200330 Supplement: ,
Verlag American Academy of Neurology
Verlagsort Minneapolis, Minn.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)