Genome Sequencing for the Diagnosis of Rare Disorders: The Brazilian Rare Genomes Project

Genome Sequencing (GS) has emerged as a transformative tool in the diagnosis of rare diseases with complex phenotypes. This technology uncovers structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thus facilitating the understanding of the underlying genomic basis of human disorders. We enrolled 10305 patients with suspected rare diseases or hereditary cancer risk syndromes from 21 centers throughout Brazil. Their genomes were sequenced with short, paired-end reads, and diagnostic reports were provided for 9448 of these patients. The overall diagnostic yield was 35.6%, and 4.6% of all positive reports had GS-exclusive findings (e.g. short copy number variants overlapping fewer than three exons, deep intronic variants, short tandem repeats expansions, mitochondrial structural variants - usually not detected by other diagnostic tests such as exome sequencing). Preliminary analysis of transcriptome sequencing (TS) or long-read GS combined with the GS interpretation provided a small but welcome improvement in diagnostic yield (0.1% and 1.0% of positive reports, respectively). Almost 3200 variant/phenotype interpretations were submitted to ClinVar. GS is proving to be an invaluable resource for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. Therefore, GS has the potential to significantly enhance the precision of healthcare in genetically diverse populations.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2026-05-01
DOI
https://doi.org/10.1016/j.xhgg.2026.100624
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Genome Sequencing for the Diagnosis of Rare Disorders: The Brazilian Rare Genomes Project

Karla Pelegrino, Joziele de Souza Lima, Ester Silveira Ramos, Jussara Melo de Cerqueira Maia et al.
Human Genetics and Genomics Advances
Genomics and Rare Diseases
article

Genome Sequencing for the Diagnosis of Rare Disorders: The Brazilian Rare Genomes Project

Karla Pelegrino, Joziele de Souza Lima, Ester Silveira Ramos, Jussara Melo de Cerqueira Maia, Vívian Pedigone Cintra, Gabriela Pereira Campilongo, Bruna Mascaro Cordeiro de Azevedo, Anete Sevciovic Grumach, Livia Maria Silva Moura, Thiago Yoshinaga Tonholo Silva, Gustavo Santos de Oliveira, Raquel Tavares Boy da Silva, Melissa Rossi Calvão Dumas, Matheus Martinelli Lima, Têmis Maria Félix, Joana Rosa Marques Prota, Catarina Gomes, Tatiana Regia Suzana Amorim Boa Sorte, Ana Luíza Garcia Cunha, Renata Moldenhauer Minillo, Tatiana Ferreira de Almeida, Vandré Cabral Gomes Carneiro, Renata Yoshiko Yamada, Angelina Xavier Acosta, Nuria Bengala Zurro, Irma Cecília Douglas Paes Barreto, Marina de França, Ana Oliveira, Patricia Silva Mota, Rafael Lucas Muniz Guedes, José Ricardo Magliocco Ceroni, Erlane Marques Ribeiro, Marco A. Curiati, Denise P. Cavalcanti, Lucas Santos Santana, Luciana Souto Mofatto, Maria Teresinha de Oliveira Cardoso, Antônio Victor Campos Coelho, Carlos Eduardo Steiner, Maria Teresa Alves da Silva Rosa, Gabriela Borges Cherulli Colichio, Mariana Paes Leme Ferriani, Vera Maria Dantas, Rafael Sales de Albuquerque, Rodrigo Barreiro, Eduardo Perrone, Mara Lúcia Schmitz Ferreira Santos, Jessica Grasiela Araujo Espolaor, Wallace William da Silva Meireles, Giselle Maria Araujo Felix Adjuto, Anne Caroline Barbosa Teixeira, Joao Bosco Oliveira, Caio Parente Barbosa, Lúcia Helena de Oliveira Cordeiro, Carolina Dias Carlos, Anna Candida Ximenes de Mendonça Sobreira, Magda Maria Sales Carneiro Sampaio, Luiza do Amaral Virmond, Michele Patricia Migliavacca, Antonette Souto EL Husny, José Bandeira do Nascimento Junior, Caio Robledo D’Angioli Costa Quaio, Thaís Bomfim Teixeira, Marina Cadena da Matta, Carolina Araujo Moreno, Paula Brito Corrêa, Kelin Chen, Marcel Pinheiro Caraciolo, Luiza Zagne Braz, Ida Vanessa Doederlein Schwartz, Renata Martins Ribeiro da Silva, Paula Teixeira Lyra
article en

Abstract

Genome Sequencing (GS) has emerged as a transformative tool in the diagnosis of rare diseases with complex phenotypes. This technology uncovers structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thus facilitating the understanding of the underlying genomic basis of human disorders. We enrolled 10305 patients with suspected rare diseases or hereditary cancer risk syndromes from 21 centers throughout Brazil. Their genomes were sequenced with short, paired-end reads, and diagnostic reports were provided for 9448 of these patients. The overall diagnostic yield was 35.6%, and 4.6% of all positive reports had GS-exclusive findings (e.g. short copy number variants overlapping fewer than three exons, deep intronic variants, short tandem repeats expansions, mitochondrial structural variants - usually not detected by other diagnostic tests such as exome sequencing). Preliminary analysis of transcriptome sequencing (TS) or long-read GS combined with the GS interpretation provided a small but welcome improvement in diagnostic yield (0.1% and 1.0% of positive reports, respectively). Almost 3200 variant/phenotype interpretations were submitted to ClinVar. GS is proving to be an invaluable resource for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. Therefore, GS has the potential to significantly enhance the precision of healthcare in genetically diverse populations.

Human Genetics and Genomics Advances
Ministério da Saúde, Sociedade Beneficente Israelita Brasileira Albert Einstein
Openalex Percentile: Top 8%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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