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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 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.
DOI: 10.1002/humu.23699
ORCID: 0000-0002-9519-5714
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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