Whole Genome Sequencing for the Diagnosis of Rare Disorders

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Abstract
Background: Whole-Genome Sequencing (WGS) and Whole-Transcriptome Sequencing (WTS) have emerged as transformative tools in the diagnosis of rare diseases with complex phenotypes. These technologies enable deep analysis of the genome and RNA expression, uncovering structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thus facilitating the understanding of gene function and regulation. Methods: We enrolled 8966 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 7614 of these patients. Results: The overall diagnostic yield was 35.8%, with an additional 5.6% of all Positive reports including gains from WGS compared to other diagnostic tests. In patients with pathogenic/likely pathogenic copy number or structural variants, WGS provided a 10.2% increase in diagnostic yield. Almost 1900 variant/phenotype interpretations were submitted to ClinVar. Conclusion: WGS and WTS are proving to be invaluable resources for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. These technologies have the potential to significantly enhance the precision of healthcare in genetically diverse populations. Key Points for NEJM Editors and Reviewers: Scope : Largest Brazilian rare disease–focused sequencing project to date. Findings : A 35.8% diagnostic yield with notable additional detection of structural, deep intronic, non-coding, and mitochondrial variants. Impact : Shortens diagnostic odyssey for patients, enriches ClinVar with almost 1900 variant interpretations from underrepresented populations, and demonstrates potential cost-effectiveness of integrating WGS into public healthcare. These interim results underscore how national WGS programs can facilitate precision medicine, especially in genetically diverse and previously underrepresented populations.

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