Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

doi:10.1002/ajmg.a.63544

. 2024 Jun;194(6):e63544.

doi: 10.1002/ajmg.a.63544. Epub 2024 Jan 23.

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

Michele P Migliavacca¹, Joselito Sobreira^{1

2}, Diana Bermeo¹, Mireille Gomes¹, Dayse Alencar¹, Luciane Sussuchi¹, Camila Alves Souza¹, Juliana Santos Silva¹, José Eduardo Kroll¹, Matheus Burger¹, Rodrigo Guarischi-Sousa¹, Darine Villela¹, Guilherme L Yamamoto^{1

3}, Fernanda Milanezi¹, Nelson Horigoshi², Regina Grigolli Cesar², Werther Brunow de Carvalho³, Rachel Sayuri Honjo³, Debora Romeo Bertola², Chong Ae Kim³, Lucian de Souza⁴, Renato S Procianoy⁴, Rita C Silveria⁴, Carla Rosenberg¹, Roberto Giugliani^{1

4}, Gustavo Aguiar Campana¹, Cristovam Scapulatempo-Neto¹, Nara Sobreira^{1

5}

Affiliations

¹ Diagnósticos da América S.A., DASA, São Paulo, Brazil.
² Hospital Infantil Sabará, São Paulo, Brazil.
³ Instituto da Criança, Faculdade de Medicina (FMUSP), Universidade de São Paulo, São Paulo, Brazil.
⁴ Hospital das Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
⁵ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 38258498
DOI: 10.1002/ajmg.a.63544

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

Michele P Migliavacca et al. Am J Med Genet A. 2024 Jun.

. 2024 Jun;194(6):e63544.

doi: 10.1002/ajmg.a.63544. Epub 2024 Jan 23.

Authors

Affiliations

¹ Diagnósticos da América S.A., DASA, São Paulo, Brazil.
² Hospital Infantil Sabará, São Paulo, Brazil.
³ Instituto da Criança, Faculdade de Medicina (FMUSP), Universidade de São Paulo, São Paulo, Brazil.
⁴ Hospital das Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.
⁵ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 38258498
DOI: 10.1002/ajmg.a.63544

Abstract

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.

Keywords: clinical pediatrics; diagnostic yield; genetic diseases; next‐generation sequencing (NGS); trio testing; whole genome sequencing.

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References

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1. Boycott, K. M., & Ardigó, D. (2018). Addressing challenges in the diagnosis and treatment of rare genetic diseases. Nature Reviews Drug Discovery, 17, 151–152. https://doi.org/10.1038/nrd.2017.246
1. Chung, C. C., Leung, G. K., Mak, C. C., Fung, J. L., Lee, M., Pei, S. L., Mullin, H. C., Hui, V. C., Chan, J. C., Chau, J. F., & Chan, M. C. (2020). Rapid whole‐exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. The Lancet Regional Health–Western Pacific, 1, 100001.
1. Denommé‐Pichon, A. S., Vitobello, A., Olaso, R., Ziegler, A., Jeanne, M., Tran Mau‐Them, F., Couturier, V., Racine, C., Isidor, B., Poë, C., Jouan, T., Boland, A., Fin, B., Bacq‐Daian, D., Besse, C., Garde, A., Prost, A., Garret, P., Tisserant, É., … Thauvin‐Robinet, C. (2022). Accelerated genome sequencing with controlled costs for infants in intensive care units: A feasibility study in a French hospital network. European Journal of Human Genetics, 30, 567–576.

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[1] Bamshad, M. J., Nickerson, D. A., & Chong, J. X. (2019). Mendelian gene discovery: Fast and furious with No end in sight. American Journal of Human Genetics, 105, 448–455. https://doi.org/10.1016/j.ajhg.2019.07.011

[2] Bamshad, M. J., Nickerson, D. A., & Chong, J. X. (2019). Mendelian gene discovery: Fast and furious with No end in sight. American Journal of Human Genetics, 105, 448–455. https://doi.org/10.1016/j.ajhg.2019.07.011

[3] Bowling, K. M., Thompson, M. L., Finnila, C. R., Hiatt, S. M., Latner, D. R., Amaral, M. D., Lawlor, J. M. J., East, K. M., Cochran, M. E., Greve, V., Kelley, W. V., Gray, D. E., Felker, S. A., Meddaugh, H., Cannon, A., Luedecke, A., Jackson, K. E., Hendon, L. G., Janani, H. M., … Cooper, G. M. (2022). Genome sequencing as a first‐line diagnostic test for hospitalized infants. Genetics in Medicine, 24, 851–861.

[4] Bowling, K. M., Thompson, M. L., Finnila, C. R., Hiatt, S. M., Latner, D. R., Amaral, M. D., Lawlor, J. M. J., East, K. M., Cochran, M. E., Greve, V., Kelley, W. V., Gray, D. E., Felker, S. A., Meddaugh, H., Cannon, A., Luedecke, A., Jackson, K. E., Hendon, L. G., Janani, H. M., … Cooper, G. M. (2022). Genome sequencing as a first‐line diagnostic test for hospitalized infants. Genetics in Medicine, 24, 851–861.

[5] Boycott, K. M., & Ardigó, D. (2018). Addressing challenges in the diagnosis and treatment of rare genetic diseases. Nature Reviews Drug Discovery, 17, 151–152. https://doi.org/10.1038/nrd.2017.246

[6] Boycott, K. M., & Ardigó, D. (2018). Addressing challenges in the diagnosis and treatment of rare genetic diseases. Nature Reviews Drug Discovery, 17, 151–152. https://doi.org/10.1038/nrd.2017.246

[7] Chung, C. C., Leung, G. K., Mak, C. C., Fung, J. L., Lee, M., Pei, S. L., Mullin, H. C., Hui, V. C., Chan, J. C., Chau, J. F., & Chan, M. C. (2020). Rapid whole‐exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. The Lancet Regional Health–Western Pacific, 1, 100001.

[8] Chung, C. C., Leung, G. K., Mak, C. C., Fung, J. L., Lee, M., Pei, S. L., Mullin, H. C., Hui, V. C., Chan, J. C., Chau, J. F., & Chan, M. C. (2020). Rapid whole‐exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. The Lancet Regional Health–Western Pacific, 1, 100001.

[9] Denommé‐Pichon, A. S., Vitobello, A., Olaso, R., Ziegler, A., Jeanne, M., Tran Mau‐Them, F., Couturier, V., Racine, C., Isidor, B., Poë, C., Jouan, T., Boland, A., Fin, B., Bacq‐Daian, D., Besse, C., Garde, A., Prost, A., Garret, P., Tisserant, É., … Thauvin‐Robinet, C. (2022). Accelerated genome sequencing with controlled costs for infants in intensive care units: A feasibility study in a French hospital network. European Journal of Human Genetics, 30, 567–576.

[10] Denommé‐Pichon, A. S., Vitobello, A., Olaso, R., Ziegler, A., Jeanne, M., Tran Mau‐Them, F., Couturier, V., Racine, C., Isidor, B., Poë, C., Jouan, T., Boland, A., Fin, B., Bacq‐Daian, D., Besse, C., Garde, A., Prost, A., Garret, P., Tisserant, É., … Thauvin‐Robinet, C. (2022). Accelerated genome sequencing with controlled costs for infants in intensive care units: A feasibility study in a French hospital network. European Journal of Human Genetics, 30, 567–576.

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Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

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Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil

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