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Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection
Author(s) -
Cowley Mark J,
Liu YuChi,
Oliver Karen L.,
Carvill Gemma,
Myers Candace T.,
Gayevskiy Velimir,
Delatycki Martin,
Vlaskamp Danique R.M.,
Zhu Ying,
Mefford Heather,
Buckley Michael F.,
Bahlo Melanie,
Scheffer Ingrid E.,
Dinger Marcel E.,
Roscioli Tony
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23699
Subject(s) - biology , exome sequencing , genetics , genome , computational biology , reference genome , contig , whole genome sequencing , exome , cancer genome sequencing , genomics , mutation , gene
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.