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-analyze genomic data in undiagnosed patients.
Original language | English (US) |
---|---|
Pages (from-to) | 374-379 |
Number of pages | 6 |
Journal | Human mutation |
Volume | 40 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2019 |
Funding
Dr Mark Cowley, Computational Biology Group Leader, Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Randwick, NSW, 2031, Australia. Email: [email protected] ∗Present address: Children's Cancer Institute, University of New South Wales, Randwick, Sydney, Australia. Funding information W.G.S. was funded by the Kinghorn Foundation. M.J.C. was supported by Cancer Institute NSW (13/ECF/1-46) and an NSW Health Early-Mid Career Fellowship. M.B. was supported by NHMRC Program grant (ID: 1054618) and NHMRC Senior Research Fellowship (ID: 1102971). I.E.S. is supported by NHMRC Program grant (1091593, 2016–2020) and Senior Practitioner Fellowship (1104831, 2016–2020). T.R. was supported through a project grant from the NHMRC (ID:AU/1/BA51117) Communicated by Graham R. Taylor
Keywords
- clinical bioinformatics, de novo
- developmental and epileptic encephalopathy, whole genome sequencing
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)