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.
Coelho et al. (2026) studied this question.