Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

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 investi...
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Autor*in:	Sanchis-Juan, Alba [verfasserIn] Stephens, Jonathan French, Courtney E. Gleadall, Nicholas Mégy, Karyn Penkett, Christopher Shamardina, Olga Stirrups, Kathleen Delon, Isabelle Dewhurst, Eleanor Dolling, Helen Erwood, Marie Grozeva, Detelina Stefanucci, Luca Arno, Gavin Webster, Andrew R. Cole, Trevor Austin, Topun Branco, Ricardo Garcia Ouwehand, Willem H. Raymond, F. Lucy Carss, Keren J.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Genome sequencing Next-generation sequencing Complex structural variant Nanopore

Anmerkung:	© The Author(s). 2018

Übergeordnetes Werk:	Enthalten in: Genome medicine - London : BioMed Central, 2009, 10(2018), 1 vom: 07. Dez.
Übergeordnetes Werk:	volume:10 ; year:2018 ; number:1 ; day:07 ; month:12

Links:	Volltext

DOI / URN:	10.1186/s13073-018-0606-6

Katalog-ID:	SPR030667976

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520			\|a 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.
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allfields	10.1186/s13073-018-0606-6 doi (DE-627)SPR030667976 (SPR)s13073-018-0606-6-e DE-627 ger DE-627 rakwb eng Sanchis-Juan, Alba verfasserin aut Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 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. Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213 Stephens, Jonathan aut French, Courtney E. aut Gleadall, Nicholas aut Mégy, Karyn aut Penkett, Christopher aut Shamardina, Olga aut Stirrups, Kathleen aut Delon, Isabelle aut Dewhurst, Eleanor aut Dolling, Helen aut Erwood, Marie aut Grozeva, Detelina aut Stefanucci, Luca aut Arno, Gavin aut Webster, Andrew R. aut Cole, Trevor aut Austin, Topun aut Branco, Ricardo Garcia aut Ouwehand, Willem H. aut Raymond, F. Lucy aut Carss, Keren J. aut Enthalten in Genome medicine London : BioMed Central, 2009 10(2018), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:10 year:2018 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-018-0606-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 07 12
spelling	10.1186/s13073-018-0606-6 doi (DE-627)SPR030667976 (SPR)s13073-018-0606-6-e DE-627 ger DE-627 rakwb eng Sanchis-Juan, Alba verfasserin aut Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 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. Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213 Stephens, Jonathan aut French, Courtney E. aut Gleadall, Nicholas aut Mégy, Karyn aut Penkett, Christopher aut Shamardina, Olga aut Stirrups, Kathleen aut Delon, Isabelle aut Dewhurst, Eleanor aut Dolling, Helen aut Erwood, Marie aut Grozeva, Detelina aut Stefanucci, Luca aut Arno, Gavin aut Webster, Andrew R. aut Cole, Trevor aut Austin, Topun aut Branco, Ricardo Garcia aut Ouwehand, Willem H. aut Raymond, F. Lucy aut Carss, Keren J. aut Enthalten in Genome medicine London : BioMed Central, 2009 10(2018), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:10 year:2018 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-018-0606-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 07 12
allfields_unstemmed	10.1186/s13073-018-0606-6 doi (DE-627)SPR030667976 (SPR)s13073-018-0606-6-e DE-627 ger DE-627 rakwb eng Sanchis-Juan, Alba verfasserin aut Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 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. Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213 Stephens, Jonathan aut French, Courtney E. aut Gleadall, Nicholas aut Mégy, Karyn aut Penkett, Christopher aut Shamardina, Olga aut Stirrups, Kathleen aut Delon, Isabelle aut Dewhurst, Eleanor aut Dolling, Helen aut Erwood, Marie aut Grozeva, Detelina aut Stefanucci, Luca aut Arno, Gavin aut Webster, Andrew R. aut Cole, Trevor aut Austin, Topun aut Branco, Ricardo Garcia aut Ouwehand, Willem H. aut Raymond, F. Lucy aut Carss, Keren J. aut Enthalten in Genome medicine London : BioMed Central, 2009 10(2018), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:10 year:2018 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-018-0606-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 07 12
allfieldsGer	10.1186/s13073-018-0606-6 doi (DE-627)SPR030667976 (SPR)s13073-018-0606-6-e DE-627 ger DE-627 rakwb eng Sanchis-Juan, Alba verfasserin aut Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 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. Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213 Stephens, Jonathan aut French, Courtney E. aut Gleadall, Nicholas aut Mégy, Karyn aut Penkett, Christopher aut Shamardina, Olga aut Stirrups, Kathleen aut Delon, Isabelle aut Dewhurst, Eleanor aut Dolling, Helen aut Erwood, Marie aut Grozeva, Detelina aut Stefanucci, Luca aut Arno, Gavin aut Webster, Andrew R. aut Cole, Trevor aut Austin, Topun aut Branco, Ricardo Garcia aut Ouwehand, Willem H. aut Raymond, F. Lucy aut Carss, Keren J. aut Enthalten in Genome medicine London : BioMed Central, 2009 10(2018), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:10 year:2018 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-018-0606-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 07 12
allfieldsSound	10.1186/s13073-018-0606-6 doi (DE-627)SPR030667976 (SPR)s13073-018-0606-6-e DE-627 ger DE-627 rakwb eng Sanchis-Juan, Alba verfasserin aut Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 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. Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213 Stephens, Jonathan aut French, Courtney E. aut Gleadall, Nicholas aut Mégy, Karyn aut Penkett, Christopher aut Shamardina, Olga aut Stirrups, Kathleen aut Delon, Isabelle aut Dewhurst, Eleanor aut Dolling, Helen aut Erwood, Marie aut Grozeva, Detelina aut Stefanucci, Luca aut Arno, Gavin aut Webster, Andrew R. aut Cole, Trevor aut Austin, Topun aut Branco, Ricardo Garcia aut Ouwehand, Willem H. aut Raymond, F. Lucy aut Carss, Keren J. aut Enthalten in Genome medicine London : BioMed Central, 2009 10(2018), 1 vom: 07. Dez. (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:10 year:2018 number:1 day:07 month:12 https://dx.doi.org/10.1186/s13073-018-0606-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2018 1 07 12
language	English
source	Enthalten in Genome medicine 10(2018), 1 vom: 07. Dez. volume:10 year:2018 number:1 day:07 month:12
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authorswithroles_txt_mv	Sanchis-Juan, Alba @@aut@@ Stephens, Jonathan @@aut@@ French, Courtney E. @@aut@@ Gleadall, Nicholas @@aut@@ Mégy, Karyn @@aut@@ Penkett, Christopher @@aut@@ Shamardina, Olga @@aut@@ Stirrups, Kathleen @@aut@@ Delon, Isabelle @@aut@@ Dewhurst, Eleanor @@aut@@ Dolling, Helen @@aut@@ Erwood, Marie @@aut@@ Grozeva, Detelina @@aut@@ Stefanucci, Luca @@aut@@ Arno, Gavin @@aut@@ Webster, Andrew R. @@aut@@ Cole, Trevor @@aut@@ Austin, Topun @@aut@@ Branco, Ricardo Garcia @@aut@@ Ouwehand, Willem H. @@aut@@ Raymond, F. Lucy @@aut@@ Carss, Keren J. @@aut@@
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author	Sanchis-Juan, Alba
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topic_title	Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing Genome sequencing (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Complex structural variant (dpeaa)DE-He213 Nanopore (dpeaa)DE-He213
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title_sort	complex structural variants in mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing
title_auth	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 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. © The Author(s). 2018
abstractGer	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. © The Author(s). 2018
abstract_unstemmed	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. © The Author(s). 2018
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title_short	Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing
url	https://dx.doi.org/10.1186/s13073-018-0606-6
remote_bool	true
author2	Stephens, Jonathan French, Courtney E. Gleadall, Nicholas Mégy, Karyn Penkett, Christopher Shamardina, Olga Stirrups, Kathleen Delon, Isabelle Dewhurst, Eleanor Dolling, Helen Erwood, Marie Grozeva, Detelina Stefanucci, Luca Arno, Gavin Webster, Andrew R. Cole, Trevor Austin, Topun Branco, Ricardo Garcia Ouwehand, Willem H. Raymond, F. Lucy Carss, Keren J.
author2Str	Stephens, Jonathan French, Courtney E. Gleadall, Nicholas Mégy, Karyn Penkett, Christopher Shamardina, Olga Stirrups, Kathleen Delon, Isabelle Dewhurst, Eleanor Dolling, Helen Erwood, Marie Grozeva, Detelina Stefanucci, Luca Arno, Gavin Webster, Andrew R. Cole, Trevor Austin, Topun Branco, Ricardo Garcia Ouwehand, Willem H. Raymond, F. Lucy Carss, Keren J.
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doi_str	10.1186/s13073-018-0606-6
up_date	2024-07-03T19:26:32.390Z
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Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

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