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The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients

Abstract

Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.

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The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

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Acknowledgements

First, we sincerely thank all the participants in this study for their cooperation and support. We thank many doctors from our department of echocardiography and neurology, who contributed to the recruitment and clinical follow-up. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82172348); Wusong Central Hospital, Baoshan District, Shanghai;Baoshan District Health Commission Key Subject Construction Project (BSZK-2023-A18); the constructing project of clinical key disciplines in Shanghai (shslczdzk03302).

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Li Zhang and Minna Shen wrote the main manuscript text and prepared Figs. 14. Xianhong Shu, Jing Ding, Jingmin Zhou and Huandong Lin provided clinical samples, Wei Guo, Beili Wang, Chunyan Zhang and Baishen Pan designed the research. All authors reviewed the manuscript.

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Correspondence to Beili Wang or Wei Guo.

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Zhang, L., Shen, M., Shu, X. et al. The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01263-4

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