ClinSV: clinical grade structural and copy number variant detection from whole genome sequencing data

Andre E Minoche; Ben Lundie; Greg B Peters; Thomas Ohnesorg; Mark Pinese; David M Thomas; Andreas Zankl; Tony Roscioli; Nicole Schonrock; Sarah Kummerfeld; Leslie Burnett; Marcel E Dinger; Mark J Cowley

doi:10.1186/s13073-021-00841-x

ClinSV: clinical grade structural and copy number variant detection from whole genome sequencing data

Genome Med. 2021 Feb 25;13(1):32. doi: 10.1186/s13073-021-00841-x.

Authors

Andre E Minoche^#^{1

2}, Ben Lundie^#³, Greg B Peters⁴, Thomas Ohnesorg^{3

5}, Mark Pinese^{6

7}, David M Thomas^{8

9}, Andreas Zankl^{3

10

11}, Tony Roscioli^{12

13

14

15}, Nicole Schonrock^{3

5}, Sarah Kummerfeld^{3

8}, Leslie Burnett^{3

8

5

11}, Marcel E Dinger^{3

16}, Mark J Cowley^{17

18

19

20}

Affiliations

¹ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, NSW, Australia. [email protected].
² St Vincent's Clinical School, UNSW, Sydney, NSW, Australia. [email protected].
³ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, NSW, Australia.
⁴ Sydney Genome Diagnostics, The Children's Hospital at Westmead, Hawkesbury Road & Hainsworth Street, Westmead, NSW, Australia.
⁵ Genome.One, Darlinghurst, NSW, Australia.
⁶ Children's Cancer Institute, University of New South Wales, Randwick, Sydney, NSW, Australia.
⁷ School of Women's and Children's Health, UNSW, Sydney, NSW, Australia.
⁸ St Vincent's Clinical School, UNSW, Sydney, NSW, Australia.
⁹ The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, NSW, Australia.
¹⁰ Department of Clinical Genetics, The Children's Hospital at Westmead, Hawkesbury Road, Westmead, NSW, Australia.
¹¹ Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia.
¹² NSW Health Pathology Randwick, Sydney, NSW, Australia.
¹³ Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.
¹⁴ Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
¹⁵ Neuroscience Research Australia, University of New South Wales, Randwick, Sydney, NSW, Australia.
¹⁶ School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia.
¹⁷ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, NSW, Australia. [email protected].
¹⁸ St Vincent's Clinical School, UNSW, Sydney, NSW, Australia. [email protected].
¹⁹ Children's Cancer Institute, University of New South Wales, Randwick, Sydney, NSW, Australia. [email protected].
²⁰ School of Women's and Children's Health, UNSW, Sydney, NSW, Australia. [email protected].

^# Contributed equally.

Abstract

Whole genome sequencing (WGS) has the potential to outperform clinical microarrays for the detection of structural variants (SV) including copy number variants (CNVs), but has been challenged by high false positive rates. Here we present ClinSV, a WGS based SV integration, annotation, prioritization, and visualization framework, which identified 99.8% of simulated pathogenic ClinVar CNVs > 10 kb and 11/11 pathogenic variants from matched microarrays. The false positive rate was low (1.5-4.5%) and reproducibility high (95-99%). In clinical practice, ClinSV identified reportable variants in 22 of 485 patients (4.7%) of which 35-63% were not detectable by current clinical microarray designs. ClinSV is available at https://github.com/KCCG/ClinSV .

Keywords: Clinical genome; Copy number variation; Microarray; Rare disease; Structural variation; Whole genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations / genetics*
Gene Frequency / genetics
Humans
Molecular Sequence Annotation
Mutation / genetics
Reproducibility of Results
Software*
Whole Genome Sequencing*