Abstract
Genomic technologies, such as targeted, exome and short-read genome sequencing approaches, have revolutionized the care of patients with rare genetic diseases. However, more than half of patients remain without a diagnosis. Emerging approaches from research-based settings such as long-read genome sequencing and optical genome mapping hold promise for improving the identification of disease-causal genetic variants. In addition, new omic technologies that measure the transcriptome, epigenome, proteome or metabolome are showing great potential for variant interpretation. As genetic testing options rapidly expand, the clinical community needs to be mindful of their individual strengths and limitations, as well as remaining challenges, to select the appropriate diagnostic test, correctly interpret results and drive innovation to address insufficiencies. If used effectively — through truly integrative multi-omics approaches and data sharing — the resulting large quantities of data from these established and emerging technologies will greatly improve the interpretative power of genetic and genomic diagnostics for rare diseases.
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Acknowledgements
The authors acknowledge the Care4Rare Canada Consortium (funded by Genome Canada and the Canadian Institutes of Health Research (CIHR) under grant OGI-0147) for providing the opportunity to collectively study undiagnosed rare diseases. K.M.B. was supported by a CIHR Foundation Grant (FDN-154279) and a Tier 1 Canada Research Chair in Rare Disease Precision Health.
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Related links
Atlas of Variant Effects: https://www.varianteffect.org
ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/
dGTEx: https://dgtex.org/
ENCODE: https://www.encodeproject.org/
Gene Matcher: https://genematcher.org/
Matchmaker Exchange: https://www.matchmakerexchange.org/
OMIM: https://www.omim.org/
Undiagnosed Diseases Network: https://undiagnosed.hms.harvard.edu/
Glossary
- Epigenomics
-
Genome-wide assessment of epigenetic marks, such as DNA methylation and histone modifications, or chromatin accessibility to determine their functional effect on gene expression. In the context of rare diseases, aberrant epigenetic patterns have been associated with disease in patients.
- Exome sequencing
-
Selective sequencing of the coding portion of the genome.
- Functional assays
-
Testing that aims to assess the effect of a variant on messenger RNA and/or protein function.
- Gene panel
-
Selective sequencing of targeted regions of the genome to examine a specific set of genes associated with a particular rare disease or a group of related rare diseases.
- Genome sequencing
-
Untargeted sequencing of the entire genome.
- Germline variants
-
Variants beginning in the sperm or egg and present in all cells in the body.
- Lipidomics
-
Assessment of a targeted subset or all lipid species in a specific specimen.
- Matchmaking
-
Approach whereby researchers input their suspected novel disease gene and some basic information (for example, phenotype and zygosity) in an effort to identify unrelated patients with the same condition and variants in the same gene to support disease association.
- Metabolomics
-
Assessment of a targeted subset or all metabolites in a specific specimen.
- Multi-omics
-
Analysis in which multiple omics modalities, such as genomics, transcriptomics, epigenomics, proteomics and metabolomics, are analysed for a given sample.
- Proteomics
-
Assessment of a targeted subset or all proteins in a specific specimen.
- RNA sequencing
-
(RNA-seq). Assessment of all messenger RNAs in a sample aimed at assessing both expression levels and mRNA splicing.
- Second-tier test
-
Testing performed to clarify the results of an initial genetic test.
- Variants of unknown significance
-
(VUS). Genetic variants or mutations whose clinical significance or effect on health is uncertain.
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Cite this article
Kernohan, K.D., Boycott, K.M. The expanding diagnostic toolbox for rare genetic diseases. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-023-00683-w
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DOI: https://doi.org/10.1038/s41576-023-00683-w
