Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing
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 an...
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doaj-e563cd1c639d49d89247155d92c3c0842020-11-25T01:23:27ZengBMCGenome Medicine1756-994X2018-12-0110111010.1186/s13073-018-0606-6Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencingAlba Sanchis-Juan0Jonathan Stephens1Courtney E. French2Nicholas Gleadall3Karyn Mégy4Christopher Penkett5Olga Shamardina6Kathleen Stirrups7Isabelle Delon8Eleanor Dewhurst9Helen Dolling10Marie Erwood11Detelina Grozeva12Luca Stefanucci13Gavin Arno14Andrew R. Webster15Trevor Cole16Topun Austin17Ricardo Garcia Branco18Willem H. Ouwehand19F. Lucy Raymond20Keren J. Carss21Department of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Paediatrics, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeCambridge University Hospitals NHS Foundation TrustDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of CambridgeDepartment of Haematology, University of CambridgeUCL Institute of Ophthalmology, University College LondonUCL Institute of Ophthalmology, University College LondonWest Midlands Genomic Medicine Centre, University Hospitals BirminghamCambridge University Hospitals NHS Foundation TrustCambridge University Hospitals NHS Foundation TrustDepartment of Haematology, University of CambridgeNIHR BioResource, Cambridge University Hospitals NHS Foundation TrustDepartment of Haematology, University of CambridgeAbstract 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.http://link.springer.com/article/10.1186/s13073-018-0606-6Genome sequencingNext-generation sequencingComplex structural variantNanoporeARID1BHNRNPU |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alba Sanchis-Juan Jonathan Stephens Courtney E. French Nicholas Gleadall Karyn Mégy Christopher Penkett Olga Shamardina Kathleen Stirrups Isabelle Delon Eleanor Dewhurst Helen Dolling Marie Erwood Detelina Grozeva Luca Stefanucci Gavin Arno Andrew R. Webster Trevor Cole Topun Austin Ricardo Garcia Branco Willem H. Ouwehand F. Lucy Raymond Keren J. Carss |
spellingShingle |
Alba Sanchis-Juan Jonathan Stephens Courtney E. French Nicholas Gleadall Karyn Mégy Christopher Penkett Olga Shamardina Kathleen Stirrups Isabelle Delon Eleanor Dewhurst Helen Dolling Marie Erwood Detelina Grozeva Luca Stefanucci Gavin Arno Andrew R. Webster Trevor Cole Topun Austin Ricardo Garcia Branco Willem H. Ouwehand F. Lucy Raymond Keren J. Carss Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing Genome Medicine Genome sequencing Next-generation sequencing Complex structural variant Nanopore ARID1B HNRNPU |
author_facet |
Alba Sanchis-Juan Jonathan Stephens Courtney E. French Nicholas Gleadall Karyn Mégy Christopher Penkett Olga Shamardina Kathleen Stirrups Isabelle Delon Eleanor Dewhurst Helen Dolling Marie Erwood Detelina Grozeva Luca Stefanucci Gavin Arno Andrew R. Webster Trevor Cole Topun Austin Ricardo Garcia Branco Willem H. Ouwehand F. Lucy Raymond Keren J. Carss |
author_sort |
Alba Sanchis-Juan |
title |
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
title_short |
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
title_full |
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
title_fullStr |
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
title_full_unstemmed |
Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
title_sort |
complex structural variants in mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2018-12-01 |
description |
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. |
topic |
Genome sequencing Next-generation sequencing Complex structural variant Nanopore ARID1B HNRNPU |
url |
http://link.springer.com/article/10.1186/s13073-018-0606-6 |
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