Three years of clinical experience with a genome-wide cfDNA screening test for aneuploidies and copy-number variants

Abstract Purpose Pregnant women have unprecedented choices for prenatal screening and testing. Cell-free DNA (cfDNA) offers the option to screen for aneuploidy of all chromosomes and genome-wide copy-number variants (CNVs), expanding screening beyond the common trisomies (“traditional” cfDNA). We sought to review the utilization trends and clinical performance characteristics of a commercially available genome-wide cfDNA test, with a subset having available diagnostic testing outcomes. Methods Retrospective analysis of 55,517 samples submitted for genome-wide cfDNA screening at a commercial laboratory, assessing indications, demographics, results, and performance. The cohort was broken into three “testing years”’ to compare trends. Results Indications shifted over time, with a decrease in referrals for ultrasound findings (22.0% to 12.0%) and an increase in no known high-risk indication (3.0% to 16.6%). Of the positive results, 25% would be missed with traditional cfDNA screening. High sensitivity and specificity were observed with a positive predictive value (PPV) of 72.6% for genome-wide CNVs and 22.4% for rare autosomal trisomies (RATs). Conclusion A broader patient population is utilizing genome-wide cfDNA, yet positivity rates and the contribution of genome-wide events have remained stable at approximately 5% and 25%, respectively. Test performance in a real-world clinical population shows high PPVs in those CNVs tested, with diagnostic outcomes in over 40% of positive cases.

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Genome-wide cell-free DNA screening: a focus on copy-number variants

Genetics in Medicine ◽

10.1038/s41436-021-01227-5 ◽

2021 ◽

Author(s):

Jill Rafalko ◽

Erica Soster ◽

Samantha Caldwell ◽

Eyad Almasri ◽

Thomas Westover ◽

...

Keyword(s):

Copy Number ◽

Chromosomal Abnormalities ◽

Diagnostic Testing ◽

Copy Number Variants ◽

Cell Free Dna ◽

Predictive Values ◽

Free Dna ◽

Genome Wide ◽

Cfdna Screening ◽

Diagnostic Outcomes

Abstract Purpose Of 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. Methods Cases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. Results CNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1–79.5%) and 71.8% (95% CI: 65.5–77.4%) for “fetal-only” events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5–68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6–97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. Conclusion Genome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

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A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

Human Molecular Genetics ◽

10.1093/hmg/dds476 ◽

2012 ◽

Vol 22 (4) ◽

pp. 816-824 ◽

Cited By ~ 20

Author(s):

Jade Chapman ◽

Elliott Rees ◽

Denise Harold ◽

Dobril Ivanov ◽

Amy Gerrish ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Copy Number ◽

Disease Risk ◽

Copy Number Variants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Study

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Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

10.1101/651299 ◽

2019 ◽

Cited By ~ 2

Author(s):

Lisa-Marie Niestroj ◽

Daniel P. Howrigan ◽

Eduardo Perez-Palma ◽

Elmo Saarentaus ◽

Peter Nürnberg ◽

...

Keyword(s):

Copy Number ◽

Genetic Architecture ◽

Focal Epilepsy ◽

Copy Number Variants ◽

Epileptic Encephalopathy ◽

Additional Risk ◽

Genome Wide ◽

A Genome ◽

Generalized Epilepsy ◽

Genome Wide Study

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

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A Genome-Wide Screen Of Functional Dna Copy Number Variants Identifies Several Novel Asthma Genes

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6173 ◽

2011 ◽

Author(s):

Angela J. Rogers ◽

Jen-Hwa Chu ◽

Katayoon Darvishi ◽

Iuliana Ionita-Laza ◽

Barbara J. Klanderman ◽

...

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Dna Copy Number ◽

Genome Wide ◽

A Genome ◽

Functional Dna ◽

Dna Copy Number Variants

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Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects

Brain ◽

10.1093/brain/awaa171 ◽

2020 ◽

Vol 143 (7) ◽

pp. 2106-2118 ◽

Cited By ~ 2

Author(s):

Lisa-Marie Niestroj ◽

Eduardo Perez-Palma ◽

Daniel P Howrigan ◽

Yadi Zhou ◽

Feixiong Cheng ◽

...

Keyword(s):

Copy Number ◽

Focal Epilepsy ◽

Copy Number Variants ◽

Epileptic Encephalopathy ◽

Human Interactome ◽

Genome Wide ◽

A Genome ◽

Wide Scale ◽

Generalized Epilepsy ◽

First Time

Abstract Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

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A genome-wide scan of copy number variants using high-density SNPs in Brown Swiss dairy cattle

Livestock Science ◽

10.1016/j.livsci.2016.08.006 ◽

2016 ◽

Vol 191 ◽

pp. 153-160 ◽

Cited By ~ 19

Author(s):

R.T.M.M. Prinsen ◽

M.G. Strillacci ◽

F. Schiavini ◽

E. Santus ◽

A. Rossoni ◽

...

Keyword(s):

Dairy Cattle ◽

Copy Number ◽

Copy Number Variants ◽

High Density ◽

Brown Swiss ◽

Genome Wide ◽

A Genome ◽

Genome Wide Scan

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A genome-wide assessment of rare copy number variants in colorectal cancer

Oncotarget ◽

10.18632/oncotarget.4621 ◽

2015 ◽

Vol 6 (28) ◽

pp. 26411-26423 ◽

Cited By ~ 7

Author(s):

Zhenli Li ◽

Dan Yu ◽

Meifu Gan ◽

Qiaonan Shan ◽

Xiaoyang Yin ◽

...

Keyword(s):

Colorectal Cancer ◽

Copy Number ◽

Copy Number Variants ◽

Genome Wide ◽

A Genome

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Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104913 ◽

2017 ◽

Vol 55 (3) ◽

pp. 181-188 ◽

Cited By ~ 4

Author(s):

Lai Fun Thean ◽

Yee Syuen Low ◽

Michelle Lo ◽

Yik-Ying Teo ◽

Woon-Puay Koh ◽

...

Keyword(s):

Colorectal Cancer ◽

Association Study ◽

Copy Number ◽

Genome Wide Association Study ◽

Copy Number Variants ◽

Genome Wide Association ◽

Copy Number Loss ◽

Genome Wide ◽

A Genome

BackgroundMultiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC.MethodsA genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests.ResultsA rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47 and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8 was significantly associated with dysregulation of several genes that perturb the Wnt, TP53 and inflammatory pathways.ConclusionsA rare CNVR at 14q11 encompassing the chromatin modifier CHD8 was significantly associated with sporadic CRC risk. Copy number loss at CHD8 altered expressions of genes implicated in colorectal tumourigenesis.

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