Sanchis-Juan, A;
Stephens, J;
French, CE;
Gleadall, N;
Megy, K;
Penkett, C;
Shamardina, O;
... Carss, KJ; + view all
(2018)
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.
Genome Medicine
, 10
(1)
, Article 95. 10.1186/s13073-018-0606-6.
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Arno_Complex structural variants in Mendelian disorders. Identification and breakpoint resolution using short- and long-read genome sequencing_VoR.pdf - Published Version Download (876kB) | Preview |
Abstract
BACKGROUND: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. METHODS: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. RESULTS: We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. CONCLUSIONS: Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.
| Type: | Article |
|---|---|
| Title: | Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13073-018-0606-6 |
| Publisher version: | https://doi.org/10.1186/s13073-018-0606-6 |
| Language: | English |
| Additional information: | © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Genome sequencing, Next-generation sequencing, Complex structural variant, Nanopore, ARID1B, HNRNPU, CEP78, CDKL5 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10071523 |
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