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

被引：103

作者：

Sanchis-Juan, Alba ^{[1
,2
]}

Stephens, Jonathan ^{[1
,2
]}

French, Courtney E. ^{[3
]}

Gleadall, Nicholas ^{[1
,2
]}

Megy, Karyn ^{[1
,2
]}

Penkett, Christopher ^{[1
,2
]}

Shamardina, Olga ^{[1
,2
]}

Stirrups, Kathleen ^{[1
,2
]}

Delon, Isabelle ^{[4
]}

Dewhurst, Eleanor ^{[1
,2
]}

Dolling, Helen ^{[1
,2
]}

Erwood, Marie ^{[1
,2
]}

Grozeva, Detelina ^{[5
]}

Stefanucci, Luca ^{[1
,6
,7
]}

Arno, Gavin ^{[8
,9
]}

Webster, Andrew R. ^{[8
,9
]}

Cole, Trevor ^{[10
]}

Austin, Topun ^{[4
]}

Branco, Ricardo Garcia ^{[4
]}

Ouwehand, Willem H. ^{[1
,2
]}

Raymond, F. Lucy ^{[1
,2
,5
]}

Carss, Keren J. ^{[1
,2
]}

机构：

[1] Univ Cambridge, NHS Blood & Transplant Ctr, Dept Haematol, Cambridge CB2 0PT, England

[2] Cambridge Univ Hosp NHS Fdn Trust, NIHR BioResource, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[3] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England

[4] Cambridge Univ Hosp NHS Fdn Trust, Cambridge CB2 0QQ, England

[5] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England

[6] Natl Hlth Serv Blood & Transplant NHSBT, Cambridge Biomed Campus, Cambridge CB2 0PT, England

[7] Addenbrookes Hosp, Div Cardiovasc Med, BHF Ctr Excellence, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[8] UCL, UCL Inst Ophthalmol, London EC1V 9EL, England

[9] Moorfields Eye Hosp NHS Trust, London EC1V 2PD, England

[10] Univ Hosp Birmingham, West Midlands Genom Med Ctr, Birmingham, W Midlands, England

来源：

GENOME MEDICINE | 2018年 / 10卷

关键词：

Genome sequencing; Next-generation sequencing; Complex structural variant; Nanopore; ARID1B; HNRNPU; CEP78; CDKL5; REARRANGEMENTS; MECHANISMS; GERMLINE; MAP; GENERATION; SIGNATURES; MUTATIONS; INVERSION; GENETICS;

D O I：

10.1186/s13073-018-0606-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

BackgroundStudies 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

引用

页数：10

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