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Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

R. Koster, R. D. Brandao, D. Tserpelis, C. E. P. van Roozendaal, C. N. van Oosterhoud, Kathleen Claes (UGent) , A. D. C. Paulussen, M. Sinnema, M. Vreeburg, V van der Schoot, et al.
(2021) NPJ GENOMIC MEDICINE. 6(1).
Author
Organization
Abstract
Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.
Keywords
MUTATION, GENE, IDENTIFICATION, TRANSCRIPTS, GUIDELINES, DIAGNOSIS, VARIANTS, NONSENSE, SEQUENCE, DEFECTS

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MLA
Koster, R., et al. “Pathogenic Neurofibromatosis Type 1 (NF1) RNA Splicing Resolved by Targeted RNAseq.” NPJ GENOMIC MEDICINE, vol. 6, no. 1, 2021, doi:10.1038/s41525-021-00258-w.
APA
Koster, R., Brandao, R. D., Tserpelis, D., van Roozendaal, C. E. P., van Oosterhoud, C. N., Claes, K., … Blok, M. J. (2021). Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq. NPJ GENOMIC MEDICINE, 6(1). https://doi.org/10.1038/s41525-021-00258-w
Chicago author-date
Koster, R., R. D. Brandao, D. Tserpelis, C. E. P. van Roozendaal, C. N. van Oosterhoud, Kathleen Claes, A. D. C. Paulussen, et al. 2021. “Pathogenic Neurofibromatosis Type 1 (NF1) RNA Splicing Resolved by Targeted RNAseq.” NPJ GENOMIC MEDICINE 6 (1). https://doi.org/10.1038/s41525-021-00258-w.
Chicago author-date (all authors)
Koster, R., R. D. Brandao, D. Tserpelis, C. E. P. van Roozendaal, C. N. van Oosterhoud, Kathleen Claes, A. D. C. Paulussen, M. Sinnema, M. Vreeburg, V van der Schoot, C. T. R. M. Stumpel, M. P. G. Broen, L. Spruijt, M. C. J. Jongmans, S. A. J. Lesnik Oberstein, A. S. Plomp, M. Misra-Isrie, F. A. Duijkers, M. J. Louwers, R. Szklarczyk, K. W. J. Derks, H. G. Brunner, A. van den Wijngaard, M. van Geel, and M. J. Blok. 2021. “Pathogenic Neurofibromatosis Type 1 (NF1) RNA Splicing Resolved by Targeted RNAseq.” NPJ GENOMIC MEDICINE 6 (1). doi:10.1038/s41525-021-00258-w.
Vancouver
1.
Koster R, Brandao RD, Tserpelis D, van Roozendaal CEP, van Oosterhoud CN, Claes K, et al. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq. NPJ GENOMIC MEDICINE. 2021;6(1).
IEEE
[1]
R. Koster et al., “Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq,” NPJ GENOMIC MEDICINE, vol. 6, no. 1, 2021.
@article{8727616,
  abstract     = {{Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.}},
  articleno    = {{95}},
  author       = {{Koster, R. and Brandao, R. D. and Tserpelis, D. and van Roozendaal, C. E. P. and van Oosterhoud, C. N. and Claes, Kathleen and Paulussen, A. D. C. and Sinnema, M. and Vreeburg, M. and van der Schoot, V and Stumpel, C. T. R. M. and Broen, M. P. G. and Spruijt, L. and Jongmans, M. C. J. and Oberstein, S. A. J. Lesnik and Plomp, A. S. and Misra-Isrie, M. and Duijkers, F. A. and Louwers, M. J. and Szklarczyk, R. and Derks, K. W. J. and Brunner, H. G. and van den Wijngaard, A. and van Geel, M. and Blok, M. J.}},
  issn         = {{2056-7944}},
  journal      = {{NPJ GENOMIC MEDICINE}},
  keywords     = {{MUTATION,GENE,IDENTIFICATION,TRANSCRIPTS,GUIDELINES,DIAGNOSIS,VARIANTS,NONSENSE,SEQUENCE,DEFECTS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{10}},
  title        = {{Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq}},
  url          = {{http://doi.org/10.1038/s41525-021-00258-w}},
  volume       = {{6}},
  year         = {{2021}},
}
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