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ACMG secondary findings in the Brazilian rare genomes project: insights from 5402 genome sequencing

Journal of Human Genetics volume 70, pages 415–420 (2025)Cite this article

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Abstract

Secondary findings (SF) are pathogenic or likely pathogenic variants in genes unrelated to the primary purpose of genetic testing. The American College of Medical Genetics (ACMG) provides guidelines on which SF should be reported, involving 81 genes linked to different conditions. With the increasing use of genome sequencing (GS), SF are more frequently detected, presenting challenges for healthcare systems. The Brazilian population is often underrepresented in genomic studies, which limits population-specific knowledge. This study aimed to outline the profile of SF in the Brazilian Rare Genomes Project (BRGP). We analyzed retrospectively SF (ACMG) data from GS of 5402 BRGP individuals. Of the 5316 cases who consented to receive SF, 3.6% (191 cases) had at least one SF. The most common genes identified were TTR, TTN, and BRCA2. SF were mainly related to cardiovascular conditions (40.2%) and cancer predisposition (37.6%). Some variants, such as TTR: c.424G>A; p. (Val142Ile) and TP53: c.1010G>A; p. (Arg337His), were recurrent, reflecting population-specific traits and founder effects. Novel variants were 10.6% of SF. SF rate varies across studies and populations. While SF can aid early diagnosis, their relevance is debated due to potential psychological and healthcare burdens. Effective genetic counseling and public health policies are essential.

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References

  1. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–74. https://doi.org/10.1038/gim.2013.73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, et al. ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25:100866. https://doi.org/10.1016/j.gim.2023.100866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Elfatih A, Saad C, The Qatar Genome Program Research Consortium, Qatar Genome Project Management, Ismail S, Al-Muftah W, et al. Analysis of 14,392 whole genomes reveals 3.5% of Qataris carry medically actionable variants. Eur J Hum Genet. 2024;32:1465–73. https://doi.org/10.1038/s41431-024-01656-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gordon AS, Zouk H, Venner E, Eng CM, Funke BH, Amendola LM, et al. Frequency of genomic secondary findings among 21,915 eMERGE network participants. Genet Med. 2020;22:1470–7. https://doi.org/10.1038/s41436-020-0810-9.

    Article  PubMed Central  Google Scholar 

  5. Saeidian AH, March ME, Youssefian L, Watson DJ, Bhandari E, Wang X, et al. Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants. Genet Med. 2024;26:101225. https://doi.org/10.1016/j.gim.2024.101225.

    Article  CAS  PubMed  Google Scholar 

  6. Quaio CRDC, Moreira CM, Novo-Filho GM, Sacramento-Bobotis PR, Groenner Penna M, Perazzio SF, et al. Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. Am J Med Genet C Semin Med Genet. 2020;184:955–64. https://doi.org/10.1002/ajmg.c.31860.

    Article  CAS  PubMed  Google Scholar 

  7. Naslavsky MS, Yamamoto GL, Almeida TF, Ezquina SAM, Sunaga DY, Pho N, et al. Exomic variants of an elderly cohort of Brazilians in the ABraOM database. Hum Mutat. 2017;38:751–63. https://doi.org/10.1002/humu.23220.

    Article  CAS  PubMed  Google Scholar 

  8. Naslavsky MS, Scliar MO, Yamamoto GL, Wang JYT, Zverinova S, Karp T, et al. Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil. Nat Commun. 2022;13. https://doi.org/10.1038/s41467-022-28648-3

  9. Coelho AVC, Mascaro-Cordeiro B, Lucon DR, Nóbrega MS, Reis RS, de Alexandre RB, et al. The Brazilian Rare Genomes Project: Validation of whole genome sequencing for rare diseases diagnosis. Front Mol Biosci. 2022;9. https://doi.org/10.3389/fmolb.2022.821582

  10. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564–9. https://doi.org/10.1002/humu.22981.

    Article  CAS  Google Scholar 

  11. McGowan-Jordan J, Hastings RJ, Moore S. ISCN 2020: an international system for human cytogenomic nomenclature. Cytogenetic Genome Res. 2020:160;7–8.

  12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen. Genet Med. 2020;22:245–57. https://doi.org/10.1038/s41436-019-0686-8.

    Article  PubMed  Google Scholar 

  14. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55. https://doi.org/10.1038/gim.2016.190.

    Article  PubMed  Google Scholar 

  15. Miller DT, Lee K, Chung WK, Gordon AS, Herman GE, Klein TE, et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:1381–90. https://doi.org/10.1038/s41436-021-01172-3.

    Article  PubMed  Google Scholar 

  16. Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, et al. ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24:1407–14. https://doi.org/10.1016/j.gim.2022.04.006.

    Article  CAS  PubMed  Google Scholar 

  17. Nolan J, Buchanan J, Taylor J, Almeida J, Bedenham T, Blair E, et al. Secondary (additional) findings from the 100,000 Genomes Project: disease manifestation, health care outcomes, and costs of disclosure. Genet Med. 2024;26:101051. https://doi.org/10.1016/j.gim.2023.101051.

    Article  CAS  PubMed  Google Scholar 

  18. Kim Y, Kim J-M, Cho H-W, Park H-Y, Park M-H. Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study. Hum Genet. 2023;142:1561–9. https://doi.org/10.1007/s00439-023-02592-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Aloraini T, Alsubaie L, Alasker S, Al Muitiri A, Alswaid A, Eyiad W, et al. The rate of secondary genomic findings in the Saudi population. Am J Med Genet A. 2022;188:83–88. https://doi.org/10.1002/ajmg.a.62491.

    Article  CAS  PubMed  Google Scholar 

  20. Johnston JJ, Brennan M-L, Radenbaugh B, Yoo SJ, Hernandez SM, NHGRI Reverse Phenotyping Core, et al. The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort. Genet Med. 2022;24:736–43. https://doi.org/10.1016/j.gim.2021.11.012.

    Article  CAS  PubMed  Google Scholar 

  21. Yamashita T, Hamidi Asl K, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. Amyloid. 2005;12:127–30. https://doi.org/10.1080/13506120500107162.

    Article  CAS  PubMed  Google Scholar 

  22. Censo 2022. Gov.br. 2022. https://www.ibge.gov.br/estatisticas/sociais/trabalho/22827-censo-demografico-2022.html. Accessed 28 Jan2025.

  23. Skrahin A, Cheema HA, Hussain M, Rana NN, Rehman KU, Kumar R, et al. Secondary findings in a large Pakistani cohort tested with whole genome sequencing. Life Sci Alliance. 2023;6:e202201673. https://doi.org/10.26508/lsa.202201673.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Garritano S, Gemignani F, Palmero EI, Olivier M, Martel-Planche G, Le Calvez-Kelm F, et al. Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Hum Mutat. 2010;31:143–50. https://doi.org/10.1002/humu.21151.

    Article  CAS  PubMed  Google Scholar 

  25. Corrêa TS, Asprino PF, de Oliveira ESC, Leite ACR, Weis L, Achatz MI, et al. TP53 p.R337H germline variant among women at risk of hereditary breast cancer in a public health system of Midwest Brazil. Genes. 2024;15:928 https://doi.org/10.3390/genes15070928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hunter JE, Jenkins CL, Bulkley JE, Gilmore MJ, Lee K, Pak CM, et al. ClinGen’s Pediatric Actionability Working Group: clinical actionability of secondary findings from genome-scale sequencing in children and adolescents. Genet Med. 2022;24:1328–35. https://doi.org/10.1016/j.gim.2022.02.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Virgens CSDAS. Variantes genéticas nos genes BRCA1 e BRCA2 em uma população da Bahia. Ufba.br. 2023. https://biologia.ufba.br/sites/biologia.ufba.br/files/tcc_final_-_cleiton_santos_das_virgens_.pdf. Accessed 28 Jan 2025.

  28. Palmero EI, Carraro DM, Alemar B, Moreira MAM, Ribeiro-Dos-Santos Â, Abe-Sandes K, et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018;8:9188. https://doi.org/10.1038/s41598-018-27315-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mazzonetto P, Milanezi F, D’Andrea M, Martins S, Monfredini PM, Dos Santos Silva J, et al. BRCA1 and BRCA2 germline mutation analysis from a cohort of 1267 patients at high risk for breast cancer in Brazil. Breast Cancer Res Treat. 2023;199:127–36. https://doi.org/10.1007/s10549-023-06892-5.

    Article  CAS  PubMed  Google Scholar 

  30. de Oliveira JM, Zurro NB, Coelho AVC, Caraciolo MP, de Alexandre RB, Cervato MC, et al. The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. Eur J Hum Genet. 2022;30:818–23. https://doi.org/10.1038/s41431-022-01098-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rodríguez-Salgado LE, Silva-Aldana CT, Medina-Méndez E, Bareño-Silva J, Arcos-Burgos M, Silgado-Guzmán DF, et al. Frequency of actionable Exomic secondary findings in 160 Colombian patients: Impact in the healthcare system. Gene. 2022;838:146699. https://doi.org/10.1016/j.gene.2022.146699.

    Article  CAS  PubMed  Google Scholar 

  32. Aarabi M, Darabi H, Bashar A, Bellissimo D, Rajkovic A, Yatsenko SA. Copy-number variants in the ACMG secondary finding genes: a reporting framework for clinical cytogeneticists. Genet Med Open. 2024;2:101839. https://doi.org/10.1016/j.gimo.2024.101839.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yatsenko SA, Aarabi M, Hu J, Surti U, Ortiz D, Madan-Khetarpal S, et al. Copy number alterations involving 59 ACMG-recommended secondary findings genes. Clin Genet. 2020;98:577–88. https://doi.org/10.1111/cge.13852.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to express our gratitude to the participants of this study and their families. This research was made possible by the data and findings provided by the Rare Genomes Project, an initiative of the Hospital Israelita Albert Einstein (HIAE) in collaboration with the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI-SUS) of the Brazilian Ministry of Health (Law 12.101/2009). We also extend our thanks to the reference participant centers involved in this project.

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  1. These authors contributed equally: Eduardo Perrone, Luiza Virmond.

Authors and Affiliations

  1. Laboratório Clínico, Hospital Israelita Albert Einstein, Av. Albert Einstein 627, São Paulo, SP, CEP 05652-000, Brasil

    Eduardo Perrone, Luiza Virmond, Antonio Victor Campos Coelho, Marina De França, Carolina Araujo Moreno, Joana Rosa Marques Prota, Jessica Grasiela de Araujo Espolaor, Michele Migliavacca, Thiago Yoshinaga Tonholo Silva, Caio Robledo D’Angioli Costa Quaio, José Ricardo Magliocco Ceroni, Kelin Chen, Renata Moldenhauer Minillo, Anne Caroline Barbosa Teixeira, Renata Yoshiko Yamada, Vivian Pedigone Cintra, Lucas Santos de Santana, Gabriela Pereira Campilongo, Renata Martins Ribeiro da Silva, Karla de Oliveira Pelegrino & Tatiana Ferreira de Almeida

  2. Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, CEP 04023-000, Brasil

    Eduardo Perrone

  3. Hospital das Clínicas de Bauru/Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Rua Silvio Marchione 3-20, Bauru, SP, CEP 17012-900, Brasil

    Luiza Virmond

  4. Neogenomica, Rua Frei Matias Teves 285, Recife, 50070-465, Brasil

    João Bosco de Oliveira Filho

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  1. Eduardo Perrone
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Contributions

EP and LV contributed to conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing - original draft, and writing - review & editing; AVCC, MF, CAM, JRMP, JGAE, MM, TYTS, CRACQ, JRMC, KC, RMM, ACBT, RYY, VPC, LSS, GPC, RMRS contributed to writing - review & editing; KOP, JBOF e TFA contributed to project administration and funding acquisition. All authors approved the final draft.

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Correspondence to Eduardo Perrone.

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Perrone, E., Virmond, L., Coelho, A.V.C. et al. ACMG secondary findings in the Brazilian rare genomes project: insights from 5402 genome sequencing. J Hum Genet 70, 415–420 (2025). https://doi.org/10.1038/s10038-025-01349-7

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