Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement

The recommended practice for individuals suspected of a genetic etiology for disorders including unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) involves a genetic testing workflow including chromosomal microar...

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Main Authors: Hayk Barseghyan, Andy Wing Chun Pang, Benjamin Clifford, Moises A. Serrano, Alka Chaubey, Alex R. Hastie
Format: Article
Language:English
Published: MDPI AG 2023-09-01
Series:Genes
Subjects:
Online Access:https://www.mdpi.com/2073-4425/14/10/1868
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author Hayk Barseghyan
Andy Wing Chun Pang
Benjamin Clifford
Moises A. Serrano
Alka Chaubey
Alex R. Hastie
author_facet Hayk Barseghyan
Andy Wing Chun Pang
Benjamin Clifford
Moises A. Serrano
Alka Chaubey
Alex R. Hastie
author_sort Hayk Barseghyan
collection DOAJ
description The recommended practice for individuals suspected of a genetic etiology for disorders including unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) involves a genetic testing workflow including chromosomal microarray (CMA), Fragile-X testing, karyotype analysis, and/or sequencing-based gene panels. Since genomic imbalances are often found to be causative, CMA is recommended as first tier testing for many indications. Optical genome mapping (OGM) is an emerging next generation cytogenomic technique that can detect not only copy number variants (CNVs), triploidy and absence of heterozygosity (AOH) like CMA, but can also define the location of duplications, and detect other structural variants (SVs), including balanced rearrangements and repeat expansions/contractions. This study compares OGM to CMA for clinically reported genomic variants, some of these samples also have structural characterization by fluorescence in situ hybridization (FISH). OGM was performed on IRB approved, de-identified specimens from 55 individuals with genomic abnormalities previously identified by CMA (61 clinically reported abnormalities). SVs identified by OGM were filtered by a control database to remove polymorphic variants and against an established gene list to prioritize clinically relevant findings before comparing with CMA and FISH results. OGM results showed 100% concordance with CMA findings for pathogenic variants and 98% concordant for all pathogenic/likely pathogenic/variants of uncertain significance (VUS), while also providing additional insight into the genomic structure of abnormalities that CMA was unable to provide. OGM demonstrates equivalent performance to CMA for CNV and AOH detection, enhanced by its ability to determine the structure of the genome. This work adds to an increasing body of evidence on the analytical validity and ability to detect clinically relevant abnormalities identified by CMA. Moreover, OGM identifies translocations, structures of duplications and complex CNVs intractable by CMA, yielding additional clinical utility.
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spelling doaj.art-85ab7dda6d024406a9dfce6b86c61c122023-11-16T10:29:36ZengMDPI AGGenes2073-44252023-09-011410186810.3390/genes14101868Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant RefinementHayk Barseghyan0Andy Wing Chun Pang1Benjamin Clifford2Moises A. Serrano3Alka Chaubey4Alex R. Hastie5Bionano, San Diego, CA 92121, USABionano, San Diego, CA 92121, USABionano, San Diego, CA 92121, USABionano Laboratories, Salt Lake City, UT 84109, USABionano, San Diego, CA 92121, USABionano, San Diego, CA 92121, USAThe recommended practice for individuals suspected of a genetic etiology for disorders including unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) involves a genetic testing workflow including chromosomal microarray (CMA), Fragile-X testing, karyotype analysis, and/or sequencing-based gene panels. Since genomic imbalances are often found to be causative, CMA is recommended as first tier testing for many indications. Optical genome mapping (OGM) is an emerging next generation cytogenomic technique that can detect not only copy number variants (CNVs), triploidy and absence of heterozygosity (AOH) like CMA, but can also define the location of duplications, and detect other structural variants (SVs), including balanced rearrangements and repeat expansions/contractions. This study compares OGM to CMA for clinically reported genomic variants, some of these samples also have structural characterization by fluorescence in situ hybridization (FISH). OGM was performed on IRB approved, de-identified specimens from 55 individuals with genomic abnormalities previously identified by CMA (61 clinically reported abnormalities). SVs identified by OGM were filtered by a control database to remove polymorphic variants and against an established gene list to prioritize clinically relevant findings before comparing with CMA and FISH results. OGM results showed 100% concordance with CMA findings for pathogenic variants and 98% concordant for all pathogenic/likely pathogenic/variants of uncertain significance (VUS), while also providing additional insight into the genomic structure of abnormalities that CMA was unable to provide. OGM demonstrates equivalent performance to CMA for CNV and AOH detection, enhanced by its ability to determine the structure of the genome. This work adds to an increasing body of evidence on the analytical validity and ability to detect clinically relevant abnormalities identified by CMA. Moreover, OGM identifies translocations, structures of duplications and complex CNVs intractable by CMA, yielding additional clinical utility.https://www.mdpi.com/2073-4425/14/10/1868optical genome mappingOGMSaphyrchromosomal microarrayCMASVs
spellingShingle Hayk Barseghyan
Andy Wing Chun Pang
Benjamin Clifford
Moises A. Serrano
Alka Chaubey
Alex R. Hastie
Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
Genes
optical genome mapping
OGM
Saphyr
chromosomal microarray
CMA
SVs
title Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
title_full Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
title_fullStr Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
title_full_unstemmed Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
title_short Comparative Benchmarking of Optical Genome Mapping and Chromosomal Microarray Reveals High Technological Concordance in CNV Identification and Additional Structural Variant Refinement
title_sort comparative benchmarking of optical genome mapping and chromosomal microarray reveals high technological concordance in cnv identification and additional structural variant refinement
topic optical genome mapping
OGM
Saphyr
chromosomal microarray
CMA
SVs
url https://www.mdpi.com/2073-4425/14/10/1868
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