Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection
AuthorCowley, MJ; Liu, Y-C; Oliver, KL; Carvill, G; Myers, CT; Gayevskiy, V; Delatycki, M; Vlaskamp, DRM; Zhu, Y; Mefford, H; ...
Source TitleHuman Mutation
University of Melbourne Author/sScheffer, Ingrid; Bahlo, Melanie; Broderick, Karen; Delatycki, Martin; Liu, Yu-Chi
AffiliationMedicine and Radiology
Melbourne School of Population and Global Health
School of Mathematics and Statistics
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsCowley, M. J., Liu, Y. -C., Oliver, K. L., Carvill, G., Myers, C. T., Gayevskiy, V., Delatycki, M., Vlaskamp, D. R. M., Zhu, Y., Mefford, H., Buckley, M. F., Bahlo, M., Scheffer, I. E., Dinger, M. E. & Roscioli, T. (2019). Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection. HUMAN MUTATION, 40 (4), pp.374-379. https://doi.org/10.1002/humu.23699.
Access StatusOpen Access
Rapid advances in genomic technologies have facilitated the identification pathogenic variants causing human disease. We report siblings with developmental and epileptic encephalopathy due to a novel, shared heterozygous pathogenic 13 bp duplication in SYNGAP1 (c.435_447dup, p.(L150Vfs*6)) that was identified by whole genome sequencing (WGS). The pathogenic variant had escaped earlier detection via two methodologies: whole exome sequencing and high-depth targeted sequencing. Both technologies had produced reads carrying the variant, however, they were either not aligned due to the size of the insertion or aligned to multiple major histocompatibility complex (MHC) regions in the hg19 reference genome, making the critical reads unavailable for variant calling. The WGS pipeline followed different protocols, including alignment of reads to the GRCh37 reference genome, which lacks the additional MHC contigs. Our findings highlight the benefit of using orthogonal clinical bioinformatic pipelines and all relevant inheritance patterns to re-analyze genomic data in undiagnosed patients.
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