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Advances of Optical Genome Mapping in Human Genetics
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Advances of Optical Genome Mapping in Human Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Technologies and Resources for Genetics".

Deadline for manuscript submissions: closed (20 September 2024) | Viewed by 8674

Special Issue Editors

Dr. Paul Dremsek

E-Mail Website
Guest Editor
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria
Interests: cytogenomics; optical genome mapping; clinical genetics; prenatal diagnostics
Dr. Anna Schachner

E-Mail Website
Guest Editor
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria
Interests: cytogenomics; optical genome mapping; clinical genetics; stem cell research

Special Issue Information

Dear Colleagues,

Optical genome mapping (OGM) is a relatively young technology for the genome-wide detection and characterization of all types of chromosomal structural variants. It is able to encompass a wide range of variant sizes, with up to 1000× greater resolution compared to karyotyping, which is accomplished by analyzing ultra-long DNA molecules.

The number of users of this promising technique has grown rapidly in recent years and includes members of the fields of constitutional genetics, cancer genomics and basic research. So far, OGM has been successfully introduced in cancer diagnostics. Furthermore, it was shown to be a promising tool in constitutional genetics, mainly for complementing existing analytical workflows, although several stand-alone findings have been reported as well.

The most topical questions in the community are whether and to what extent OGM competes with existing technologies, in what indications and areas of applications the use of OGM is the most effective, and the technology's current limitations. Additionally, for the clinical realm, questions regarding reproducibility and standardized mode of interpretation arise.

This Special Issue intends to compile the insights, results and knowledge of the small but ever-growing community of researchers and clinical laboratories utilizing OGM. This should help to define more clearly the viable applications of OGM and its prospective role in the toolkit of cytogenomics.

In this Special Issue, original research articles, case studies and reviews are welcome.

We look forward to receiving your contributions.

Dr. Paul Dremsek
Dr. Anna Schachner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • optical genome mapping
  • cytogenomics
  • chromosomal structural variation
  • clinical genetics
  • cancer genetics
  • prenatal diagnostics
  • population genetics

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Published Papers (6 papers)

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11 pages, 4431 KiB  
Article
Optical Genome Mapping Reveals Complex and Cryptic Rearrangement Involving PML::RARA Fusion in Acute Promyelocytic Leukemia
by Melanie Klausner, Victoria Stinnett, Jen Ghabrial, Laura Morsberger, Natalie DeMetrick, Patty Long, Jing Zhu, Kirstin Smith, Trisha James, Emily Adams and Ying S. Zou
Genes 2024, 15(11), 1402; https://doi.org/10.3390/genes15111402 - 30 Oct 2024
Viewed by 470
Abstract
Background/objectives: Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML), characterized by the hallmark translocation t(15;17) resulting in a PML::RARA fusion. Once diagnosed, APL is now considered to be one of the most treatable forms of AML. [...] Read more.
Background/objectives: Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML), characterized by the hallmark translocation t(15;17) resulting in a PML::RARA fusion. Once diagnosed, APL is now considered to be one of the most treatable forms of AML. However, without early detection and treatment, the disease is associated with rapid deterioration and lethal side effects. Methods: We describe a case of diagnostic APL presenting with a normal karyotype, normal RARA break-apart FISH, and unclear, atypical PML/RARA FISH findings. We used optical genome mapping (OGM) to characterize this atypical PML/RARA fusion. Results: OGM allowed for detection of a PML::RARA fusion resulting from a cryptic and complex insertion of PML::RARA into RARA on 17q21.2 whereby a segment of 15q24.1 was inserted into the 17q21.2. The recipient breakpoint of the insertion was at intron 2 of the RARA gene and the donor breakpoint of the insertion was at exon 5/intron 6 of the PML gene. Conclusions: This is the first report of an insertional PML::RARA fusion into the RARA gene on 17q detected by OGM. OGM has demonstrated its utility in a clinical cytogenetics environment, allowing for clearer characterization and diagnosis of various neoplasms. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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13 pages, 5488 KiB  
Article
Characterization of the Rat Osteosarcoma Cell Line UMR-106 by Long-Read Technologies Identifies a Large Block of Amplified Genes Associated with Human Disease
by Alan F. Scott, David W. Mohr, William A. Littrell, Reshma Babu, Michelle Kokosinski, Victoria Stinnett, Janvi Madhiwala, John Anderson, Ying S. Zou and Kathleen L. Gabrielson
Genes 2024, 15(10), 1254; https://doi.org/10.3390/genes15101254 - 26 Sep 2024
Viewed by 788
Abstract
Background/Objectives: The rat osteosarcoma cell line UMR-106 is widely used for the study of bone cancer biology but it has not been well characterized with modern genomic methods. Methods: To better understand the biology of UMR-106 cells we used a combination of optical [...] Read more.
Background/Objectives: The rat osteosarcoma cell line UMR-106 is widely used for the study of bone cancer biology but it has not been well characterized with modern genomic methods. Methods: To better understand the biology of UMR-106 cells we used a combination of optical genome mapping (OGM), long-read sequencing nanopore sequencing and RNA sequencing.The UMR-106 genome was compared to a strain-matched Sprague-Dawley rat for variants associated with human osteosarcoma while expression data were contrasted with a public osteoblast dataset. Results: Using the COSMIC database to identify the most affected genes in human osteosarcomas we found somatic mutations in Tp53 and H3f3a. OGM identified a relatively small number of differences between the cell line and a strain-matched control animal but did detect a ~45 Mb block of amplification that included Myc on chromosome 7 which was confirmed by long-read sequencing. The amplified region showed several blocks of non-contiguous rearranged sequence implying complex rearrangements during their formation and included 14 genes reported as biomarkers in human osteosarcoma, many of which also showed increased transcription. A comparison of 5mC methylation from the nanopore reads of tumor and control samples identified genes with distinct differences including the OS marker Cdkn2a. Conclusions: This dataset illustrates the value of long DNA methods for the characterization of cell lines and how inter-species analysis can inform us about the genetic nature underlying mutations that underpin specific tumor types. The data should be a valuable resource for investigators studying osteosarcoma, in general, and specifically the UMR-106 model. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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16 pages, 1382 KiB  
Article
A Comparison of Structural Variant Calling from Short-Read and Nanopore-Based Whole-Genome Sequencing Using Optical Genome Mapping as a Benchmark
by Yang Pei, Melanie Tanguy, Adam Giess, Abhijit Dixit, Louise C. Wilson, Richard J. Gibbons, Stephen R. F. Twigg, Greg Elgar and Andrew O. M. Wilkie
Genes 2024, 15(7), 925; https://doi.org/10.3390/genes15070925 - 16 Jul 2024
Cited by 1 | Viewed by 1917
Abstract
The identification of structural variants (SVs) in genomic data represents an ongoing challenge because of difficulties in reliable SV calling leading to reduced sensitivity and specificity. We prepared high-quality DNA from 9 parent–child trios, who had previously undergone short-read whole-genome sequencing (Illumina platform) [...] Read more.
The identification of structural variants (SVs) in genomic data represents an ongoing challenge because of difficulties in reliable SV calling leading to reduced sensitivity and specificity. We prepared high-quality DNA from 9 parent–child trios, who had previously undergone short-read whole-genome sequencing (Illumina platform) as part of the Genomics England 100,000 Genomes Project. We reanalysed the genomes using both Bionano optical genome mapping (OGM; 8 probands and one trio) and Nanopore long-read sequencing (Oxford Nanopore Technologies [ONT] platform; all samples). To establish a “truth” dataset, we asked whether rare proband SV calls (n = 234) made by the Bionano Access (version 1.6.1)/Solve software (version 3.6.1_11162020) could be verified by individual visualisation using the Integrative Genomics Viewer with either or both of the Illumina and ONT raw sequence. Of these, 222 calls were verified, indicating that Bionano OGM calls have high precision (positive predictive value 95%). We then asked what proportion of the 222 true Bionano SVs had been identified by SV callers in the other two datasets. In the Illumina dataset, sensitivity varied according to variant type, being high for deletions (115/134; 86%) but poor for insertions (13/58; 22%). In the ONT dataset, sensitivity was generally poor using the original Sniffles variant caller (48% overall) but improved substantially with use of Sniffles2 (36/40; 90% and 17/23; 74% for deletions and insertions, respectively). In summary, we show that the precision of OGM is very high. In addition, when applying the Sniffles2 caller, the sensitivity of SV calling using ONT long-read sequence data outperforms Illumina sequencing for most SV types. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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8 pages, 745 KiB  
Article
Optical Genome Mapping Reveals Disruption of the RASGRF2 Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation
by Rosa Catalina Lederbogen, Sabine Hoffjan, Charlotte Thiels, Ulrike Angelika Mau-Holzmann, Sylke Singer, Maria Viktorovna Yusenko, Hoa Huu Phuc Nguyen and Wanda Maria Gerding
Genes 2024, 15(6), 809; https://doi.org/10.3390/genes15060809 - 19 Jun 2024
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Abstract
While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation [...] Read more.
While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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11 pages, 4894 KiB  
Article
Optical Genome Mapping as a Potential Routine Clinical Diagnostic Method
by Hayk Barseghyan, Doris Eisenreich, Evgenia Lindt, Martin Wendlandt, Florentine Scharf, Anna Benet-Pages, Kai Sendelbach, Teresa Neuhann, Angela Abicht, Elke Holinski-Feder and Udo Koehler
Genes 2024, 15(3), 342; https://doi.org/10.3390/genes15030342 - 7 Mar 2024
Cited by 2 | Viewed by 2091
Abstract
Chromosome analysis (CA) and chromosomal microarray analysis (CMA) have been successfully used to diagnose genetic disorders. However, many conditions remain undiagnosed due to limitations in resolution (CA) and detection of only unbalanced events (CMA). Optical genome mapping (OGM) has the potential to address [...] Read more.
Chromosome analysis (CA) and chromosomal microarray analysis (CMA) have been successfully used to diagnose genetic disorders. However, many conditions remain undiagnosed due to limitations in resolution (CA) and detection of only unbalanced events (CMA). Optical genome mapping (OGM) has the potential to address these limitations by capturing both structural variants (SVs) resulting in copy number changes and balanced rearrangements with high resolution. In this study, we investigated OGM’s concordance using 87 SVs previously identified by CA, CMA, or Southern blot. Overall, OGM was 98% concordant with only three discordant cases: (1) uncalled translocation with one breakpoint in a centromere; (2) uncalled duplication with breakpoints in the pseudoautosomal region 1; and (3) uncalled mosaic triplication originating from a marker chromosome. OGM provided diagnosis for three previously unsolved cases: (1) disruption of the SON gene due to a balanced reciprocal translocation; (2) disruption of the NBEA gene due to an inverted insertion; (3) disruption of the TSC2 gene due to a mosaic deletion. We show that OGM is a valid method for the detection of many types of SVs in a single assay and is highly concordant with legacy cytogenomic methods; however, it has limited SV detection capabilities in centromeric and pseudoautosomal regions. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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8 pages, 992 KiB  
Brief Report
Evaluation of Optical Genome Mapping in Clinical Genetic Testing of Facioscapulohumeral Muscular Dystrophy
by Anja Kovanda, Luca Lovrečić, Gorazd Rudolf, Ivana Babic Bozovic, Helena Jaklič, Lea Leonardis and Borut Peterlin
Genes 2023, 14(12), 2166; https://doi.org/10.3390/genes14122166 - 30 Nov 2023
Viewed by 1634
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy, caused by the contraction of the D4Z4 repeats on the permissive 4qA haplotype on chromosome 4, resulting in the faulty expression of the DUX4 gene. Traditional diagnostics are based on Southern [...] Read more.
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy, caused by the contraction of the D4Z4 repeats on the permissive 4qA haplotype on chromosome 4, resulting in the faulty expression of the DUX4 gene. Traditional diagnostics are based on Southern blotting, a time- and effort-intensive method that can be affected by single nucleotide variants (SNV) and copy number variants (CNV), as well as by the similarity of the D4Z4 repeats located on chromosome 10. We aimed to evaluate optical genome mapping (OGM) as an alternative molecular diagnostic method for the detection of FSHD. We first performed optical genome mapping with EnFocus™ FSHD analysis using DLE-1 labeling and the Saphyr instrument in patients with inconclusive diagnostic Southern blot results, negative FSHD2 results, and clinically evident FSHD. Second, we performed OGM in parallel with the classical Southern blot analysis for our prospectively collected new FSHD cases. Finally, panel exome sequencing was performed to confirm the presence of FSHD2. In two patients with diagnostically inconclusive Southern blot results, OGM was able to identify shortened D4Z4 repeats on the permissive 4qA alleles, consistent with the clinical presentation. The results of the prospectively collected patients tested in parallel using Southern blotting and OGM showed full concordance, indicating that OGM is a useful alternative to the classical Southern blotting method for detecting FSHD1. In a patient showing clinical FSHD but no shortened D4Z4 repeats in the 4qA allele using OGM or Southern blotting, a likely pathogenic variant in SMCHD1 was detected using exome sequencing, confirming FSHD2. OGM and panel exome sequencing can be used consecutively to detect FSHD2. Full article
(This article belongs to the Special Issue Advances of Optical Genome Mapping in Human Genetics)
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