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Pathogenicity evaluation and the genotype–phenotype analysis of OPA1 variants

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Abstract

Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60–90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3′ terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.

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All data in this study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all participants and family members for their participation and their agreement to use their clinical data in this study.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81970837) and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology.

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Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Pediatric and Genetic Eye Clinic, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou, 510060, China

    Xingyu Xu, Panfeng Wang, Xiaoyun Jia, Wenmin Sun, Shiqiang Li, Xueshan Xiao & Qingjiong Zhang

  2. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    J. Fielding Hejtmancik

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  1. Xingyu Xu
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  2. Panfeng Wang
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  4. Wenmin Sun
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Correspondence to Qingjiong Zhang.

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All procedures in this study conformed to the tenets of the Helsinki Declaration, and was approved by the ZOC institutional review board.

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Xu, X., Wang, P., Jia, X. et al. Pathogenicity evaluation and the genotype–phenotype analysis of OPA1 variants. Mol Genet Genomics 296, 845–862 (2021). https://doi.org/10.1007/s00438-021-01783-0

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