Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing
Despite advances in genome sequencing, many individuals with rare genetic disorders remain undiagnosed. Transcriptional profiling via RNA-seq can reveal functional impacts of DNA variants and improve diagnosis. We assessed blood-derived RNA-seq in the largely undiagnosed SickKids Genome Clinic cohort (n = 134), which has been subjected to multiple analyses benchmarking the utility of genome sequencing. Our RNA-centric analysis identifies gene expression outliers, aberrant splicing, and allele-specific expression. In one-third of diagnosed individuals (20/61), RNA-seq reinforced DNA-based findings. In 2/61 cases, RNA-seq revised diagnoses (EPG5 to LZTR1 in an individual with a Noonan syndrome-like disorder) and discovered an additional relevant gene (CEP120 in addition to SON in an individual with ZTTK syndrome). Additionally, ~7% (5/73) of undiagnosed cases had at least one plausible candidate gene identified. This study highlights both the benefits and limitations of whole-blood RNA profiling in refining genetic diagnoses and uncovering novel disease mechanisms.
Authors
- Huayun Hou (ORCID: https://orcid.org/0000-0003-3971-1427)
- Michael Brudno (ORCID: https://orcid.org/0000-0001-7947-2243)
- Alper Çelik (ORCID: https://orcid.org/0000-0003-2084-5871)
- Roberto Mendoza‐Londono (ORCID: https://orcid.org/0000-0003-3542-8106)
- M. Stephen Meyn (ORCID: https://orcid.org/0000-0001-6444-2607)
- Dimitri J. Stavropoulos (ORCID: https://orcid.org/0000-0001-5498-2108)
- Meagan Gloven-Brown
- Michael Braga
- Lianna Kyriakopoulou (ORCID: https://orcid.org/0000-0001-8929-8082)
- Michael D. Wilson (ORCID: https://orcid.org/0000-0002-4015-3066)
- Kyoko E. Yuki (ORCID: https://orcid.org/0000-0003-0726-3914)
- Stephen W. Scherer (ORCID: https://orcid.org/0000-0002-8326-1999)
- Gregory Costain (ORCID: https://orcid.org/0000-0003-0099-9945)
- Sean Barnes
- Anna Szuto (ORCID: https://orcid.org/0000-0001-9140-6193)
- Christian R. Marshall (ORCID: https://orcid.org/0000-0002-4003-7671)
- Adam Shlien (ORCID: https://orcid.org/0000-0002-0368-5370)
- Arun Ramani (ORCID: https://orcid.org/0000-0002-8162-8523)
- Sarah Bowdin (ORCID: https://orcid.org/0000-0001-8477-2670)
- Ronald D. Cohn (ORCID: https://orcid.org/0000-0002-2673-696X)
- James J. Dowling (ORCID: https://orcid.org/0000-0002-9131-8529)
Institutions
- University Health Network (CA)
- University of Wisconsin–Madison (US)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Vector Institute (CA)
- SickKids Foundation (CA)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41525-025-00505-4
- Citations
- 2
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.63
Funders
- Genome Canada
- Hospital for Sick Children