Genomic Applications in Rare Disease Diagnosis

Rare diseases collectively affect millions globally yet present unique diagnostic challenges due to their low prevalence and clinical heterogeneity. Genomic technologies have revolutionised rare disease investigation by enabling the rapid identification of pathogenic variants across the genome or exome. Approaches range from targeted gene panels to whole-exome sequencing (WES) and whole-genome sequencing (WGS), often complemented by transcriptome sequencing, copy number analysis and functional assays. Recent advances in long-read sequencing and integrative multi-omics strategies have increased diagnostic yield and reduced time to result, informing precision treatment, reproductive counselling and patient management. Computational frameworks, including phenotype-driven variant prioritisation and standardised variant classification guidelines, support interpretation. Implementation of these tools within clinical workflows—alongside structured phenotype ontologies—has demonstrated substantial clinical utility, altering acute and long-term care pathways for a significant proportion of patients with previously undiagnosed genetic conditions.

Research from Nature Portfolio

Recent studies have described a national programme combining rapid WGS with transcriptome sequencing, proteomics and long-read technologies in critically ill infants and children. This integrated multi-omic approach delivered genome-wide results in under three days and achieved a diagnostic yield exceeding 50 %, enabling precision treatments, surgical planning and targeted palliation. Another investigation employed transcriptome sequencing of patient-derived fibroblasts to reveal aberrant expression, splicing events and mono-allelic variants in cases unresolved by exome analysis. This strategy uncovered novel intronic pathogenic variants and established a new disease-associated gene, illustrating the power of RNA-level data to resolve non-coding and splicing-related aetiologies.

Genomic Applications in Rare Disease Diagnosis publication trend

The graph below shows the total number of articles in genomic applications in rare disease diagnosis across all publications each year (not limited to Nature Index journals).

Technical terms

Whole-genome sequencing (WGS): Determination of the complete DNA sequence of an individual’s genome.

Whole-exome sequencing (WES): Targeted sequencing of all protein-coding regions (exons) in the genome.

Transcriptome sequencing: Sequencing of RNA transcripts to assess gene expression and splicing patterns.

Multi-omics: Integration of genomic, transcriptomic, proteomic or other high-throughput molecular data.

Diagnostic yield: Proportion of cases in which a definitive genetic diagnosis is obtained.

Chromosomal microarray (CMA): Genome-wide detection of copy number variants using hybridisation-based arrays.

References

1. Integrated multi-omics for rapid rare disease diagnosis on a national scale. Nature Medicine (2023).
2. 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. Genetics in Medicine (2015).
3. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. The Lancet (2019).
4. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Research (2013).
5. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. npj Genomic Medicine (2018).
6. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Communications (2017).
7. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. npj Genomic Medicine (2018).