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Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients

Abstract

Objectives

To delineate the disease-causing mutations of the Stargardt disease-related genes in Chinese patients diagnosed with Stargardt disease or retinitis pigmentosa (RP) by whole exome sequencing analysis.

Methods

A total of 123 sporadic RP or Stargardt disease patients and 2 Stargardt disease families were recruited. All sporadic patients and the probands of the families were subjected to whole exome sequencing analysis. The candidate mutations were verified by direct sequencing based on the cosegregation pattern and in 200 control subjects and by the bioinformatics analyses.

Results

A total of three reported ABCA4 mutations were identified in the probands of the two Stargardt disease families. The probands and the affected family members with either homozygous or compound heterozygous mutations showed typical Stargardt disease features, which was absent in their unaffected family members. The cosegregation pattern confirmed the mode of recessive inheritance. Moreover, two sporadic Stargardt disease patients were identified to carry two novel ABCA4 and one PROM1 mutations. In addition, 13 novel variants were found in 119 sporadic RP patients in 7 Stargardt disease-related genes, and 8 novel missense variants were conserved across different species and predicted to be damaging to the protein. All 15 novel variants were absent in our 200 control subjects.

Conclusions

This study revealed 22.4% study subjects carrying Stargardt disease-related gene mutations with total 15 novel variants in seven Stargardt disease-related genes, assuring that targeted next-generation sequencing analysis is a high throughput strategy to facilitate the clinical diagnosis from suspicious patients and recommended as a routine examination for inherited retinal dystrophies.

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Fig. 1: Pedigrees and clinical characteristics of the two recruited Chinese Stargardt disease families.
Fig. 2: Sanger sequencing confirmation of the identified Stargardt-related gene variants from the whole exome sequencing analysis in patients with Stargardt disease or retinitis pigmentosa.
Fig. 3: Multiple sequence alignment of Stargardt-related gene protein across different species.

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Acknowledgements

The authors would like to express their deepest gratitude to all the participants in this study.

Funding

This work was supported by the Special Fund for the Innovative Science and Technology Strategy of Guangdong Province (project code: 180918154960752 to TKN), an internal grant from the Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong (project code: 20-020 to TKN), the National Nature Science Foundation of China (30901646 and 81170853 to HC), YangFan Program and TeZhi Program of Guangdong Province (to HC), and Grant for Key Disciplinary Project of Clinical Medicine under the Guangdong High-level University Development Program, China.

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TKN and HC: conception and design and financial support. YZ and HC: provision of study materials. YC, X-LY, SC, YX, and S-LC: collection and/or assembly of data. TKN, YC, and X-LY: data analysis and interpretation. TKN and X-LY: manuscript writing. TKN and HC: final approval of manuscript.

Corresponding author

Correspondence to Haoyu Chen.

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Ng, T.K., Cao, Y., Yuan, XL. et al. Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients. Eye 36, 749–759 (2022). https://doi.org/10.1038/s41433-021-01525-x

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