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Title: | Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection. | Austin Authors: | Cowley, Mark J;Liu, Yu-Chi;Oliver, Karen L;Carvill, Gemma;Myers, Candace T;Gayevskiy, Velimir;Delatycki, Martin B ;Vlaskamp, Danique R M;Zhu, Ying;Mefford, Heather;Buckley, Michael F;Bahlo, Melanie;Scheffer, Ingrid E ;Dinger, Marcel E;Roscioli, Tony | Affiliation: | Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Department of Medical Genetics, Royal North Shore Hospital, St Leonards, Australia Austin Health, Heidelberg, Victoria, Australia Department of Pediatrics, University of Washington, Seattle, WA, USA Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia Prince of Wales Clinical School, University of New South Wales, Sydney, Australia Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia Florey Institute, Melbourne, Australia Population Health and Immunity Division, Walter and Eliza Hall Institute, Melbourne, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia Neuroscience Research Australia, University of New South Wales, Randwick, Sydney, Australia NSW Health Pathology Randwick, Sydney, Australia |
Issue Date: | 2019 | Date: | 2018-12-17 | Publication information: | Human mutation 2019; 40(4): 374-379 | Abstract: | 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-analyse genomic data in undiagnosed patients. This article is protected by copyright. All rights reserved. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/20044 | DOI: | 10.1002/humu.23699 | ORCID: | 0000-0002-9519-5714 0000-0002-8298-8758 0000-0003-4945-3628 0000-0001-5188-6153 0000-0002-9519-5714 0000-0003-4423-934X 0000-0001-5132-0774 0000-0002-2311-2174 |
Journal: | Human mutation | PubMed URL: | 30556619 | Type: | Journal Article | Subjects: | clinical bioinformatics de novo developmental and epileptic encephalopathy whole genome sequencing |
Appears in Collections: | Journal articles |
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