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Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection


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.

Type Journal
ISBN 1098-1004 (Electronic) 1059-7794 (Linking)
Authors Cowley, 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.
Responsible Garvan Author (missing name)
Published Date 2019-04-01
Published Volume 40
Published Issue 4
Published Pages 374-379
Status Published in-print
DOI 10.1002/humu.23699
URL link to publisher's version