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Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation

Wouter Steyaert (UGent) , Lonneke Haer-Wigman, Rolph Pfundt, Debby Hellebrekers, Marloes Steehouwer, Juliet Hampstead, Elke de Boer, Alexander Stegmann, Helger Yntema, Erik-Jan Kamsteeg, et al.
(2023) NATURE COMMUNICATIONS. 14(1).
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Abstract
The short lengths of short-read sequencing reads challenge the analysis of paralogous genomic regions in exome and genome sequencing data. Most genetic variants within these homologous regions therefore remain unidentified in standard analyses. Here, we present a method (Chameleolyser) that accurately identifies single nucleotide variants and small insertions/deletions (SNVs/Indels), copy number variants and ectopic gene conversion events in duplicated genomic regions using whole-exome sequencing data. Application to a cohort of 41,755 exome samples yields 20,432 rare homozygous deletions and 2,529,791 rare SNVs/Indels, of which we show that 338,084 are due to gene conversion events. None of the SNVs/Indels are detectable using regular analysis techniques. Validation by high-fidelity long-read sequencing in 20 samples confirms >88% of called variants. Focusing on variation in known disease genes leads to a direct molecular diagnosis in 25 previously undiagnosed patients. Our method can readily be applied to existing exome data.
Keywords
COPY NUMBER VARIATION, GENE CONVERSION, SEQUENCE, EVOLUTION, ALIGNMENT

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MLA
Steyaert, Wouter, et al. “Systematic Analysis of Paralogous Regions in 41,755 Exomes Uncovers Clinically Relevant Variation.” NATURE COMMUNICATIONS, vol. 14, no. 1, 2023, doi:10.1038/s41467-023-42531-9.
APA
Steyaert, W., Haer-Wigman, L., Pfundt, R., Hellebrekers, D., Steehouwer, M., Hampstead, J., … Gilissen, C. (2023). Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation. NATURE COMMUNICATIONS, 14(1). https://doi.org/10.1038/s41467-023-42531-9
Chicago author-date
Steyaert, Wouter, Lonneke Haer-Wigman, Rolph Pfundt, Debby Hellebrekers, Marloes Steehouwer, Juliet Hampstead, Elke de Boer, et al. 2023. “Systematic Analysis of Paralogous Regions in 41,755 Exomes Uncovers Clinically Relevant Variation.” NATURE COMMUNICATIONS 14 (1). https://doi.org/10.1038/s41467-023-42531-9.
Chicago author-date (all authors)
Steyaert, Wouter, Lonneke Haer-Wigman, Rolph Pfundt, Debby Hellebrekers, Marloes Steehouwer, Juliet Hampstead, Elke de Boer, Alexander Stegmann, Helger Yntema, Erik-Jan Kamsteeg, Han Brunner, Alexander Hoischen, and Christian Gilissen. 2023. “Systematic Analysis of Paralogous Regions in 41,755 Exomes Uncovers Clinically Relevant Variation.” NATURE COMMUNICATIONS 14 (1). doi:10.1038/s41467-023-42531-9.
Vancouver
1.
Steyaert W, Haer-Wigman L, Pfundt R, Hellebrekers D, Steehouwer M, Hampstead J, et al. Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation. NATURE COMMUNICATIONS. 2023;14(1).
IEEE
[1]
W. Steyaert et al., “Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation,” NATURE COMMUNICATIONS, vol. 14, no. 1, 2023.
@article{01J3NESS9T65QKS1C7P8J4ZPAR,
  abstract     = {{The short lengths of short-read sequencing reads challenge the analysis of paralogous genomic regions in exome and genome sequencing data. Most genetic variants within these homologous regions therefore remain unidentified in standard analyses. Here, we present a method (Chameleolyser) that accurately identifies single nucleotide variants and small insertions/deletions (SNVs/Indels), copy number variants and ectopic gene conversion events in duplicated genomic regions using whole-exome sequencing data. Application to a cohort of 41,755 exome samples yields 20,432 rare homozygous deletions and 2,529,791 rare SNVs/Indels, of which we show that 338,084 are due to gene conversion events. None of the SNVs/Indels are detectable using regular analysis techniques. Validation by high-fidelity long-read sequencing in 20 samples confirms >88% of called variants. Focusing on variation in known disease genes leads to a direct molecular diagnosis in 25 previously undiagnosed patients. Our method can readily be applied to existing exome data.}},
  articleno    = {{6845}},
  author       = {{Steyaert, Wouter and Haer-Wigman, Lonneke and Pfundt, Rolph and Hellebrekers, Debby and Steehouwer, Marloes and Hampstead, Juliet and de Boer, Elke and Stegmann, Alexander and Yntema, Helger and Kamsteeg, Erik-Jan and Brunner, Han and Hoischen, Alexander and Gilissen, Christian}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{COPY NUMBER VARIATION,GENE CONVERSION,SEQUENCE,EVOLUTION,ALIGNMENT}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{13}},
  title        = {{Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation}},
  url          = {{http://doi.org/10.1038/s41467-023-42531-9}},
  volume       = {{14}},
  year         = {{2023}},
}
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