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Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant

Elke de Boer, Burcu Yaldiz, Anne-Sophie Denomme-Pichon, Leslie Matalonga, Steve Laurie, Wouter Steyaert (UGent) , Rick de Reuver, Christian Gilissen, Michael Kwint, Rolph Pfundt, et al.
(2022) EUROPEAN JOURNAL OF MEDICAL GENETICS. 65(1).
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Organization
Abstract
Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets +/- 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genomewide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.
Keywords
TUBB3, Exome sequencing, Genome-wide variant calling, Solve-RD, ERN ITHACA, MUTATIONS

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MLA
de Boer, Elke, et al. “Genome-Wide Variant Calling in Reanalysis of Exome Sequencing Data Uncovered a Pathogenic TUBB3 Variant.” EUROPEAN JOURNAL OF MEDICAL GENETICS, vol. 65, no. 1, 2022, doi:10.1016/j.ejmg.2021.104402.
APA
de Boer, E., Yaldiz, B., Denomme-Pichon, A.-S., Matalonga, L., Laurie, S., Steyaert, W., … Solve-RD-DITF-ITHACA, [missing]. (2022). Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant. EUROPEAN JOURNAL OF MEDICAL GENETICS, 65(1). https://doi.org/10.1016/j.ejmg.2021.104402
Chicago author-date
Boer, Elke de, Burcu Yaldiz, Anne-Sophie Denomme-Pichon, Leslie Matalonga, Steve Laurie, Wouter Steyaert, Rick de Reuver, et al. 2022. “Genome-Wide Variant Calling in Reanalysis of Exome Sequencing Data Uncovered a Pathogenic TUBB3 Variant.” EUROPEAN JOURNAL OF MEDICAL GENETICS 65 (1). https://doi.org/10.1016/j.ejmg.2021.104402.
Chicago author-date (all authors)
de Boer, Elke, Burcu Yaldiz, Anne-Sophie Denomme-Pichon, Leslie Matalonga, Steve Laurie, Wouter Steyaert, Rick de Reuver, Christian Gilissen, Michael Kwint, Rolph Pfundt, Alain Verloes, Michel A. A. P. Willemsen, Bert B. A. de Vries, Antonio Vitobello, Tjitske Kleefstra, Lisenka E. L. M. Vissers, [missing] Solve-RD SNV-indel Working Grp, and [missing] Solve-RD-DITF-ITHACA. 2022. “Genome-Wide Variant Calling in Reanalysis of Exome Sequencing Data Uncovered a Pathogenic TUBB3 Variant.” EUROPEAN JOURNAL OF MEDICAL GENETICS 65 (1). doi:10.1016/j.ejmg.2021.104402.
Vancouver
1.
de Boer E, Yaldiz B, Denomme-Pichon A-S, Matalonga L, Laurie S, Steyaert W, et al. Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant. EUROPEAN JOURNAL OF MEDICAL GENETICS. 2022;65(1).
IEEE
[1]
E. de Boer et al., “Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant,” EUROPEAN JOURNAL OF MEDICAL GENETICS, vol. 65, no. 1, 2022.
@article{01J8QR153CGX4GXM3D9JM8E7J8,
  abstract     = {{Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets +/- 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genomewide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.}},
  articleno    = {{104402}},
  author       = {{de Boer, Elke and Yaldiz, Burcu and Denomme-Pichon, Anne-Sophie and Matalonga, Leslie and Laurie, Steve and Steyaert, Wouter and de Reuver, Rick and Gilissen, Christian and Kwint, Michael and Pfundt, Rolph and Verloes, Alain and Willemsen, Michel A. A. P. and de Vries, Bert B. A. and Vitobello, Antonio and Kleefstra, Tjitske and Vissers, Lisenka E. L. M. and Solve-RD SNV-indel Working Grp, [missing] and Solve-RD-DITF-ITHACA, [missing]}},
  issn         = {{1769-7212}},
  journal      = {{EUROPEAN JOURNAL OF MEDICAL GENETICS}},
  keywords     = {{TUBB3,Exome sequencing,Genome-wide variant calling,Solve-RD,ERN ITHACA,MUTATIONS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{7}},
  title        = {{Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant}},
  url          = {{http://doi.org/10.1016/j.ejmg.2021.104402}},
  volume       = {{65}},
  year         = {{2022}},
}
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