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<p>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 (<i>n</i> = 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 (<i>EPG5</i> to <i>LZTR1</i> in an individual with a Noonan syndrome-like disorder) and discovered an additional relevant gene (<i>CEP120</i> in addition to <i>SON</i> 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.</p>

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Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Huayun Hou,
  • Kyoko E. Yuki,
  • Gregory Costain,
  • Anna Szuto,
  • Sierra Barnes,
  • Arun K. Ramani,
  • Alper Celik,
  • Michael Braga,
  • Meagan Gloven-Brown,
  • Dimitri J. Stavropoulos,
  • Sarah Bowdin,
  • Ronald D. Cohn,
  • Roberto Mendoza-Londono,
  • Stephen W. Scherer,
  • Michael Brudno,
  • Christian R. Marshall,
  • M. Stephen Meyn,
  • Adam Shlien,
  • James J. Dowling,
  • Michael D. Wilson,
  • Lianna Kyriakopoulou

摘要

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.