Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the <i>ND4</i> 11778G>A mutation

Yanchun Ji; Feilong Meng; Yinglong Gao; Zhipeng Nie; Yunfan He; Juanjuan Zhang; Ya Li; Minglian Zhang; Jianyong Wang; Yongming Zhang; Shihui Wei; Jun Qin Mo; Min-Xin Guan

doi:10.1016/j.jgg.2026.08.007

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Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation

doi: 10.1016/j.jgg.2026.08.007

a. Department of Genetics and Metabolic Diseases, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, Zhejiang 310051, China;
b. Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang 310058, China;
c. Center for Mitochondrial Biomedicine and Department of Ophthalmology, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China;
d. Center for Genetic Medicine, Zhejiang University International School and Institute of Medicine, Yiwu, Zhejiang 322000, China;
e. School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China;
f. Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, Hebei 054001, China;
g. Department of Ophthalmology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China;
h. Department of Ophthalmology, Chinese PLA General Hospital, Beijing 100089, China;
i. Department of Pathology, Rady Children's Hospital, University of California at San Diego, School of Medicine, San Diego, California, 92123, USA

Funds:

We are grateful to patients and their family members for their participation. This work was supported by grants from the National Key R&D Program of China (2023YFC2705603 to Y.J. and 2021YFC2700900 to M.X.G.) and the National Natural Science Foundation of China (U25A20134 to M.X.G.).

Received Date: 2026-05-11
Accepted Date: 2026-08-19
Rev Recd Date: 2026-08-12

Abstract

Abstract

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.
- Leber hereditary optic neuropathy (LHON),
- Inheritance pattern,
- Mitochondrial DNA mutation,
- Mitochondrial haplogroup,
- Nuclear modifier gene,
- Chinese

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