Dr. Yassmine Akkari and Dr. Mariam Mathew, both esteemed experts in the field of cytogenomics, have made significant strides in advancing our understanding and application of genomic technologies in clinical research. Dr. Akkari is a senior director within the Institute for Genomic Medicine at Nationwide Children’s Hospital. She is triple certified by the American Board of Medical Genetics and Genomics in the specialties of Clinical Cytogenetics, Clinical Molecular Genetics and PhD Medical Genetics. Dr. Mathew is a clinical director within the Institute for Genomic Medicine. She received her PhD at the University of Toronto, Canada where she focused on variant fusions in acute promyelocytic leukemia.   

A recent review paper, authored by Dr. Mathew and Dr. Akkari, published in Clinical Chemistry, sheds light on the current standards for prenatal sample cytogenomic assessment, existing gaps, and how optical genome mapping (OGM) can play a crucial role in enhancing the characterization of these samples. 

Prenatal genetics is a specialized field focused on analyzing the genetic makeup of a developing fetus. This discipline aims to detect genetic abnormalities that could indicate various conditions, such as chromosomal anomalies, inherited disorders, and congenital malformations. Indications for prenatal genetic assessment include advanced maternal age, abnormal ultrasound findings, family history of genetic disorders, recurrent miscarriages, and abnormal results from non-invasive prenatal testing (NIPT). Genetic analysis tools in prenatal genetics, such as karyotyping (KT), chromosomal microarray analysis (CMA), and whole-exome/-genome sequencing, aim to identify structural rearrangements, copy-number variations, single-gene mutations, and other genomic alterations that could impact the health and development of the fetus. Early detection and precise characterization of these genetic abnormalities are crucial for informed decision-making and management of the pregnancy. 

Prenatal genetic analysis traditionally relies on several methodologies, including KT, fluorescence in situ hybridization (FISH), CMA, and whole-exome/-genome sequencing. These techniques have collectively improved the detection rates of structural rearrangements and copy-number abnormalities, especially in high-risk pregnancies such as those with structural abnormalities observed in ultrasound. However, these assays are often conducted either concurrently or sequentially, leading to increased costs and extended turnaround times, which are critical factors. 

Over the past years, OGM has emerged as a significant advancement in genomic analysis for multiple disease indications, providing a high-resolution, genome-wide approach to identifying structural variants, such as deletions, gains, translocations, inversions, insertions, and large repeat expansions. Recent studies have highlighted OGM’s ability to detect unbalanced rearrangements, balanced translocations, and complex structural variations provides a more detailed understanding of the genomic landscape, which can significantly impact clinical research outcomes. OGM not only enhances the resolution for detecting these aberrations but also streamlines laboratory workflows by automating several steps traditionally performed manually, providing a more efficient workflow when compared to traditional cytogenetic methods of analysis. 

Over the past years, multiple studies have demonstrated that OGM is a powerful tool that aids researchers in uncovering the genetic etiology of reproductive health cases. It is particularly valuable in understanding the underlying genetic causes of recurrent miscarriage, infertility, and pregnancy abnormalities.  

In their review, Dr. Akkari and Dr. Mathew discuss the findings of a large prospective study led by Dr. Xie and colleagues, which demonstrated the utility of OGM in prenatal research. This study by Xie et al. includes the largest prospective OGM prenatal cohort to date, providing valuable insights into the capabilities of OGM in a clinical research setting. The study authors enrolled 204 pregnant women and compared OGM results with those of classical assays, including CMA and KT. The study highlighted that OGM had a good concordance rate with CMA (95.56%) and uncovered variants missed by CMA that included balanced translocation and better resolution of duplications,. Impressively, OGM achieved a positive finding yield of 25%, which was higher than both CMA (22%) and KT (18%). The ability of OGM to detect duplication events and determine their genomic location and orientation significantly improved variant interpretation and reduced the burden of reporting variants of uncertain significance. Finally, OGM detected additional variants not identified by karyotype and CMA, showcasing its superior resolution and capability to capture balanced rearrangements and resolve complex duplication events. 

The automation and high-resolution analysis offered by OGM address the current challenges in the genetics workforce and provide a comprehensive view of the genome, making it an essential tool for future genomic analysis methodologies. As genomic technologies continue to evolve, the integration of OGM alongside traditional methods will likely enhance the overall effectiveness and efficiency of cytogenomic assessment. 

Dr. Yassmine Akkari and Dr. Mariam Mathew’s contributions to the field of cytogenomics through their research and leadership have been instrumental in advancing the prenatal genetics field. This publication highlights the significant role of OGM in improving the detection and understanding of structural genomic variants, offering a promising future for comprehensive cytogenomic analysis in clinical prenatal research.  

For more information on Dr. Yassmine Akkari’s work and the potential of OGM in prenatal assessment, visit her profile. 

For more information on Dr. Mariam Mathew’s work, visit her profile. 

Citation 

Mathew, M. T., & Akkari, Y. M. N. (2024). Optical Genome Mapping in Prenatal Diagnosis: Democratizing Comprehensive Cytogenomic Testing. Clinical Chemistry. https://doi.org/10.1093/clinchem/hvae060.