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Cracking rare disorders : a new minimally invasive RNA-seq protocol

Laurenz De Cock, Erika D'haenens (UGent) , Lies Vantomme (UGent) , Lynn Backers, Aude Beyens (UGent) , Kathleen Claes (UGent) , Griet De Clercq (UGent) , Robin de Putter (UGent) , Candy Kumps (UGent) , Nika Schuermans (UGent) , et al.
(2025) NPJ GENOMIC MEDICINE. 10(1).
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Abstract
RNA sequencing (RNA-seq) has become key to complementing exome and genome sequencing for variant interpretation. We present a minimally invasive RNA-seq protocol using short-term cultured peripheral blood mononuclear cells (PBMCs) with and without cycloheximide treatment, enabling detection of transcripts subject to nonsense-mediated decay. While broadly applicable, this protocol is particularly suited for neurodevelopmental disorders, as up to 80% of the genes in our intellectual disability and epilepsy gene panel are expressed in PBMCs. Applied to 46 affected individuals and 15 parents, RNA-seq revealed splicing defects in six of nine individuals with splice variants, allowing reclassification of seven variants. Targeted cDNA analysis confirmed aberrant splicing in four individuals but missed intron retention in two. Global analyses (FRASER, OUTRIDER, and monoallelic expression) supported findings but did not yield new diagnoses. We propose a flowchart integrating RNA-seq into diagnostic workflows. Overall, our protocol is easily implementable, captures complex splicing events, and enhances variant classification.
Keywords
DECAY, GENOMICS, VISUALIZATION, EXPRESSION, VARIANTS, CDKN1C

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MLA
De Cock, Laurenz, et al. “Cracking Rare Disorders : A New Minimally Invasive RNA-Seq Protocol.” NPJ GENOMIC MEDICINE, vol. 10, no. 1, 2025, doi:10.1038/s41525-025-00502-7.
APA
De Cock, L., D’haenens, E., Vantomme, L., Backers, L., Beyens, A., Claes, K., … Menten, B. (2025). Cracking rare disorders : a new minimally invasive RNA-seq protocol. NPJ GENOMIC MEDICINE, 10(1). https://doi.org/10.1038/s41525-025-00502-7
Chicago author-date
De Cock, Laurenz, Erika D’haenens, Lies Vantomme, Lynn Backers, Aude Beyens, Kathleen Claes, Griet De Clercq, et al. 2025. “Cracking Rare Disorders : A New Minimally Invasive RNA-Seq Protocol.” NPJ GENOMIC MEDICINE 10 (1). https://doi.org/10.1038/s41525-025-00502-7.
Chicago author-date (all authors)
De Cock, Laurenz, Erika D’haenens, Lies Vantomme, Lynn Backers, Aude Beyens, Kathleen Claes, Griet De Clercq, Robin de Putter, Candy Kumps, Nika Schuermans, Jo Sourbron, Hannes Syryn, Simon Tavernier, Eva Vanbelleghem, Olivier Vanakker, Bart Vandekerckhove, Tim Van Damme, Bert Callewaert, Annelies Dheedene, Sarah Vergult, and Björn Menten. 2025. “Cracking Rare Disorders : A New Minimally Invasive RNA-Seq Protocol.” NPJ GENOMIC MEDICINE 10 (1). doi:10.1038/s41525-025-00502-7.
Vancouver
1.
De Cock L, D’haenens E, Vantomme L, Backers L, Beyens A, Claes K, et al. Cracking rare disorders : a new minimally invasive RNA-seq protocol. NPJ GENOMIC MEDICINE. 2025;10(1).
IEEE
[1]
L. De Cock et al., “Cracking rare disorders : a new minimally invasive RNA-seq protocol,” NPJ GENOMIC MEDICINE, vol. 10, no. 1, 2025.
@article{01JWQYEM74S6JPDQ4PXSE0EYEB,
  abstract     = {{RNA sequencing (RNA-seq) has become key to complementing exome and genome sequencing for variant interpretation. We present a minimally invasive RNA-seq protocol using short-term cultured peripheral blood mononuclear cells (PBMCs) with and without cycloheximide treatment, enabling detection of transcripts subject to nonsense-mediated decay. While broadly applicable, this protocol is particularly suited for neurodevelopmental disorders, as up to 80% of the genes in our intellectual disability and epilepsy gene panel are expressed in PBMCs. Applied to 46 affected individuals and 15 parents, RNA-seq revealed splicing defects in six of nine individuals with splice variants, allowing reclassification of seven variants. Targeted cDNA analysis confirmed aberrant splicing in four individuals but missed intron retention in two. Global analyses (FRASER, OUTRIDER, and monoallelic expression) supported findings but did not yield new diagnoses. We propose a flowchart integrating RNA-seq into diagnostic workflows. Overall, our protocol is easily implementable, captures complex splicing events, and enhances variant classification.}},
  articleno    = {{45}},
  author       = {{De Cock, Laurenz and D'haenens, Erika and Vantomme, Lies and Backers, Lynn and Beyens, Aude and Claes, Kathleen and De Clercq, Griet and de Putter, Robin and Kumps, Candy and Schuermans, Nika and Sourbron, Jo and Syryn, Hannes and Tavernier, Simon and Vanbelleghem, Eva and Vanakker, Olivier and Vandekerckhove, Bart and Van Damme, Tim and Callewaert, Bert and Dheedene, Annelies and Vergult, Sarah and Menten, Björn}},
  issn         = {{2056-7944}},
  journal      = {{NPJ GENOMIC MEDICINE}},
  keywords     = {{DECAY,GENOMICS,VISUALIZATION,EXPRESSION,VARIANTS,CDKN1C}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{14}},
  title        = {{Cracking rare disorders : a new minimally invasive RNA-seq protocol}},
  url          = {{http://doi.org/10.1038/s41525-025-00502-7}},
  volume       = {{10}},
  year         = {{2025}},
}
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