Abstract
Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders.
Highlights
Global medical associations, such as the American College of Obstetrics and Gynecology (ACOG), the International Society of Ultrasound and Obstetrics and Gynecology (ISUOG), and the American College of Medical Genetics and Genomics (ACMG), recommend prenatal genetic testing that includes screening with non-invasive prenatal testing 4.0/).(NIPT) and invasive diagnostic testing be offered to all pregnant women, irrespective of the gestation age and maternal age [1,2,3]
An assay based on Optical genome mapping (OGM) with the Saphyr system, a commercially available platform for genome analysis from Bionano Genomics has been developed to utilize either direct or cultured amniotic fluid cells or chorionic villus samples (CVS), which are used in clinical practice for the current standard of care methods such as karyotyping, fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA)
With its power to detect all classes of structural variations (SVs), including copy number variations (CNVs), at a higher resolution than traditional cytogenetic methods can play a significant role in prenatal care and management as a next-generation cytogenomic tool
Summary
Global medical associations, such as the American College of Obstetrics and Gynecology (ACOG), the International Society of Ultrasound and Obstetrics and Gynecology (ISUOG), and the American College of Medical Genetics and Genomics (ACMG), recommend prenatal genetic testing that includes screening with non-invasive prenatal testing. OGM performed with the Saphyr® system demonstrated a clinical concordance of 100% when compared to combined cytogenetic analysis for the detection of 100 abnormalities in a cohort of 85 patients with constitutional disorders that included several sample types such as amniocytes, CVS and lymphoblastoid cells [11]. Genes 2021, 12, 398 study aimed to detect all clinically relevant SVs reported by multiple methods, including karyotyping, CMA, and FISH, in leukemias from bone marrow or peripheral blood from 48 cases. Multiple studies have demonstrated the performance of OGM and its ability to stand out as a unique technology for the detection of all classes of clinically significant genome-wide SVs. Here, we present the methodology and the application of OGM in the prenatal setting, with classical examples of several syndromic SVs that are important for the diagnosis and detection of prenatal genetic disorders
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