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

Minoche, André E.; Lundie, Ben; Peters, Greg; Ohnesorg, Thomas; Pinese, Mark; Thomas, David M.; Zankl, Andreas; Roscioli, Tony; Schönrock, Nicole; Kummerfeld, Sarah; Burnett, Leslie; Dinger, Marcel E.; Cowley, Mark J.

doi:10.1186/s13073-021-00841-x

Cited by 50 publications

(34 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tool can be used to inspect structural variants observed in the sample, especially deletions and copy number changes. This approach can be helpful in a manual verification of structural variants, which is still a recommended practice in medical genetics [8]. Finally, eXNVerify gives insight into the sample's usefulness in a hypothesis-free analysis of pathogenic variants.…”

Section: Resultsmentioning

confidence: 99%

eXNVerify: coverage analysis for long and short-read sequencing data in clinical context

Porębski

Stokowy

2021

Preprint

View full text Add to dashboard Cite

Accurate identification of genetic variants to a large extent is based on type of experimental technology, quality of the material and coverage of obtained sequencing data. Our motivation was to create a tool that will evaluate genome coverage and accelerate the introduction of long-read sequencing to medical diagnostics and clinical practice. Here we present eXNVerify: a tool for inspection of clinical data in the context of pathogenic variants. The tool calculates Clinical Depth Coverage – a measure of coverage which we introduce to evaluate loci with pathogenic germline and somatic variants reported in ClinVar. The tool additionally provides visualization options for user-defined genes of interest. Finally, we present an examples of BRCA1, TP53, CFTR application and results of a test conducted in the Extensive Sequence Dataset of Gold-Standard Samples for Benchmarking and Development. eXNVerify is available at https://github.com/porebskis/eXNVerify and can be directly pulled from the DockerHub repository: docker pull porebskis/exnverify:1.0.

show abstract

Section: Resultsmentioning

confidence: 99%

eXNVerify: coverage analysis for long and short-read sequencing data in clinical context

Porębski

Stokowy

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Libraries were generated using either Illumina TrueSeq PCR-free or TrueSeq Nano. Alignment, variant calling, and annotation was performed as described previously (65–67).…”

Section: Methodsmentioning

confidence: 99%

“…Libraries were generated using either Illumina TrueSeq PCR-free or TrueSeq Nano. Alignment, variant calling, and annotation was performed as described previously (65)(66)(67). Mice To generate Tnfaip3 246tr and Tnfaip3 I207L strains, respective guide RNAs (5ʹ-GGGATATCTGTAACACTCC -3ʹ and 5ʹ-TGACAATGATGGGTCTTCTGAGG-3ʹ) were microinjected into C57BL/6 zygotes in combination with Cas9 mRNA.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Environmental and genetic disease modifiers of haploinsufficiency of A20

Zammit

Gray

Siggs

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Monogenic diseases can often manifest diverse clinical phenotypes and cause diagnostic dilemmas. While monoallelic loss-of-function variants in TNFAIP3 (Haploinsufficiency of A20; HA20) cause a highly penetrant autoinflammatory disease, the variable expressivity suggest a role for additional genetic and environmental disease modifiers. Here, we identify critically ill children who inherited a family-specific TNFAIP3 deletion from one of their otherwise healthy parents. Each of the probands also inherited in trans a subtle loss-of-function I207L TNFAIP3 variant that is common in Oceania, originally introgressed from Denisovans. Modelling this compound heterozgous state in mice under specific pathogen free conditions demonstrated a reduced threshold to break immune tolerance. Exaggerated immune responses were precipitated by inheriting the two genetic hits on the TNFAIP3 checkpoint coupled with increasing the microbial challenge to immune tolerance, either by co-housing with pet store mice carrying a wild microbial burden or by transient dietary exposure to a chemical that diminishes the intestinal mucin barrier separating gut microbes from immune sensing systems. These data illuminate second-hit genetic and environmental modifiers contributing to complex inflammatory and autoimmune disease. Increased mechanistic understanding of the presence and contribution of disease modifiers will aid diagnostic and prognostic patient stratification and potentially reveal novel therapeutic opportunities.

show abstract

“…Genome sequencing (GS) provides homogeneous coverage, improving the detection of SNVs, CNVs, and balanced translocations [ 88 ], as well as the detection of mosaicism, when coverage depth is sufficient (e.g. a mean coverage of 130 ×) [ 80 , 89 ].…”

Section: Massive Parallel Sequencing - a Milestone Towards Id-gene Identificationmentioning

confidence: 99%

Intellectual disability genomics: current state, pitfalls and future challenges

et al. 2021

View full text Add to dashboard Cite

Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery.

show abstract

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

Cited by 50 publications

References 70 publications

eXNVerify: coverage analysis for long and short-read sequencing data in clinical context

eXNVerify: coverage analysis for long and short-read sequencing data in clinical context

Environmental and genetic disease modifiers of haploinsufficiency of A20

Intellectual disability genomics: current state, pitfalls and future challenges

Contact Info

Product

Resources

About