Evaluation of CNV detection tools for NGS panel data in genetic diagnostics

Moreno-Cabrera, José Marcos; Valle, Jesús Del; Castellanos, Elisabeth; Feliubadaló, Lídia; Pineda, Marta; Brunet, Joan; Serra, Eduard; Capellà, Gabriel; Lázaro, Conxi; Gel, Bernat

doi:10.1038/s41431-020-0675-z

Cited by 85 publications

(90 citation statements)

References 31 publications

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“…Furthermore, in a few cases, we had incomplete genetic diagnosis when variants of uncertain significance or single heterozygous variants in two PCD genes were detected, suggesting the possibility of digenic inheritance, although further studies are required to establish this with certainty. In addition, testing for the presence of copy number variants (CNVs) was not performed due to the limitation of existing tools to detect single‐ or multi‐exon alterations (Moreno‐Cabrera et al, 2020). It is possible that CNVs could explain at least some of the unresolved cases.…”

Section: Discussionmentioning

confidence: 99%

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

et al. 2021

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We aimed to determine a genetic diagnosis in the national primary ciliary dyskinesia (PCD) cohort of Cyprus, an island with a high disease prevalence. We used targeted next-generation sequencing (NGS) of 39 PCD genes in 48 patients of Greek-Cypriot and other ancestries. We achieved a molecular diagnosis in 74% of the unrelated families tested. We identified 24 different mutations in 11 genes, 12 of which are novel. Homozygosity was more common in Greek-Cypriot than non-Greek-Cypriot patients (88% vs. 46.2%, p = .016). Four mutations (DNAH11:c.5095-2A>G, CFAP300:c.95_103delGCCGGCTCC, TTC25:c.716G>A, RSPH9:c.670+2T>C) were found in 74% of the diagnosed Greek-Cypriot families. Patients with RSPH9 mutations demonstrated higher nasal nitric oxide (57 vs. 15 nl/min, p <.001), higher forced expiratory volume in 1 s (−0.89 vs. −2.37, p = .018) and forced vital capacity (−1.00 vs. −2.16, p = .029) z scores than the rest of the cohort.Targeted multigene-panel NGS is an efficient tool for early diagnosis of PCD, providing insight into genetic disease epidemiology and improved patient stratification.

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Section: Discussionmentioning

confidence: 99%

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

et al. 2021

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“…In the ICO cohort, genetic testing was performed on genomic DNA using the nextgeneration sequencing (NGS) custom panel I2HCP, which comprises 122-135 hereditary cancer (HC)-associated genes, depending on the version used [21]. Copy number analysis was performed from NGS data using DECoN [22] with parameter optimization [23]. Copy number variants (CNVs) in BARD1 were validated using custom multiplex ligationdependent probe amplification (MLPA) probes designed according to the instructions provided by MRC-Holland.…”

Section: Ngs Panel Testingmentioning

confidence: 99%

BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Rofes

Valle

Torres-Esquius

et al. 2021

Genes

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Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10–6.48; p = 1.16 × 10−5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10–7.70; p = 5.45 × 10−5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77–18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

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“…Most important is read-depth which indicates the number of separate copies of the same sequence that are read during the test. 8,9 If there are enough reads to allow a comparison of read depth between different sequences within a gene or regions within a chromosome, a change in copy number can be detected. Not all HTS platforms are able to detect CNVs and this is an important consideration for laboratories when selecting which technology to use.…”

Section: Comparison Of Sequencing Methodsmentioning

confidence: 99%

Genomic Analysis for the Detection of Bleeding and Thrombotic Disorders

Gomez

2021

Semin Thromb Hemost

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The development of high-throughput sequencing technologies has ushered in a new era of genomic testing in clinical medicine. This has greatly enhanced our diagnostic repertoire for hemostatic diseases particularly for milder or rarer bleeding disorders. New genetic causes for heritable platelet disorders have been discovered along with the recognition of clinical manifestations outside hemostasis, such as the association of leukemia with RUNX1 variation. Genome-wide association studies in heritable thrombophilia have demonstrated that some of the genetic variants that are commonly included in thrombophilia testing are of no clinical relevance, while uncovering new variants that should potentially be included. The implementation of new technology has necessitated far-reaching changes in clinical practice to deal with incidental findings, variants of uncertain significance, and genetic disease modifiers. Mild bleeding disorders that were previously considered to have a monogenic basis now appear to have an oligogenic etiology. To harness these advances in knowledge large databases have been developed to capture the new genomic information with phenotypic features on a population-wide scale. The use of this so-called “big data” requires new bioinformatics tools with the promise of delivering precision medicine in the foreseeable future. This review discusses the use of these technologies in clinical practice, the benefits of genomic testing, and some of the challenges associated with implementation.

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Evaluation of CNV detection tools for NGS panel data in genetic diagnostics

Cited by 85 publications

References 31 publications

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence

BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Genomic Analysis for the Detection of Bleeding and Thrombotic Disorders

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