The annual European Society of Human Genetics (ESHG) conference, held in Berlin from June 1 to June 4, 2024, was a significant event for the genetic research community. Among the many technologies covered in groundbreaking scientific presentations and posters, optical genome mapping (OGM) stood out as a transformative technique in the field of rare disease research. Bionano’s OGM workflow was highlighted as a tool for uncovering elusive structural variants (SVs) that often hold the key to the missing heritability in unresolved cases of rare disease.  

Structural Variants: The Missing Pieces of the Genetic Puzzle  

A central theme at ESHG 2024 was the crucial role structural variants play in understanding the genetic basis of rare diseases. Despite advances in research conducted with next-generation sequencing (NGS), many individuals with rare genetic disorders remain without a clear genetic explanation. This gap, often referred to as “missing heritability,” can be attributed to the limitations of traditional sequencing methods in detecting complex SVs.  

Structural variants, including large deletions, duplications, inversions, and translocations, are notoriously challenging to identify with conventional techniques like karyotyping, FISH, chromosomal micro–array (CMA) or Multiplex Ligation-dependent Probe Amplification (MLPA). However, Bionano OGM provides a high-resolution, genome-wide analysis of these variants, enhancing our understanding of genetic disorders.  

ESHG Presentations Highlight the Significance of Structural Variants  

The significant role SVs play in genetic research was underscored during one entire concurrent session and a dedicated workshop, both of which were fully packed with attendees (and accessible on-demand for ESHG attendees). These sessions highlighted the increasing recognition of SVs as crucial components in the genetic landscape of rare diseases and the importance of advanced techniques like OGM to their detection.  

Illuminating Rare Diseases with OGM 

Additional ESHG presentations and posters collectively showcased OGM’s ability to reveal hidden SVs in rare disease research.  

Uncovering Hidden Structural Variants  

Dr. Bart van den Sanden from Radboud UMC presented findings from the Solve-RD consortium, where OGM was utilized to uncover de novo SVs in unresolved rare disease trios. This high sensitivity and low false positive rate approach led to the identification of candidate phenotype-associated SVs in 12% of the samples, emphasizing the technique’s value in rare disease research. This trend was mirrored in several posters, where OGM revealed clinically relevant SVs that other methods had missed, particularly in complex genomic regions. For example, a study led by Andriana Valkama from the University of Oulu on myelodysplastic syndrome found OGM to be a suitable first-tier solution, capable of replacing traditional karyotyping and enhancing SV detection. In 2023, the same research group published a study showing OGM could replace FISH for Chronic Lymphocytic Leukemia (CLL) assessment.   

Enhancing Genomic Profiling 

Marlene Ek from the Karolinska Institute discussed the use of OGM for genomic profiling in multiple myeloma (MM), a condition characterized by genomic complexity and heterogeneity. In a study, OGM was able to identify previously undetected rearrangements, including missing IGH fusion partners and MYC rearrangements (presentation is available on-demand here). OGM’s ability to provide detailed genomic insights was echoed in several poster presentations, such as those from the University of Wisconsin and Newcastle University, where OGM resolved complex genomic rearrangements and identified hidden SVs, thus providing new insights into the genetic basis of rare disorders. For instance, Dr. April Hall from the University of Wisconsin presented a case of a translocation involving four chromosomes in an individual with global neurodevelopmental delays, central hypotonia, obesity, and dysmorphic facial features, conditions that eluded other sequencing technologies. Ellie McAleese-Park from Newcastle University highlighted an insertion within the first intron of the NF1 gene in a case of Neurofibromatosis type 1 (NF1) that had previously been unidentified.  

Precision in Breakpoint Identification 

The precision of OGM in identifying breakpoints was highlighted in various presentations. Dr. Erica Gerkes from the University of Groningen detailed how OGM was used to define balanced translocation breakpoints upstream of SOX9 in a sample from a subject with acampomelic campomelic dysplasia. This precision in breakpoint identification is crucial for understanding the genetic basis of such disorders and was similarly demonstrated in posters like the one from Dr. Karolina Rutkowska at the Medical University of Warsaw, where OGM detected WWOX gene insertions and deletions in cerebellar ataxias.  

Versatility Across Research Applications 

Dr. Rashmi Kanagal-Shamanna, from The University of Texas MD Anderson Cancer Center, presented at an educational session, where she highlighted the application  of OGM across various fields (available on-demand here). In hematologic research, for example, Dr. Kanagal-Shamanna shared data showing OGM’s utility as a valuable tool for analysis, risk stratification, and targeted research. The session emphasized OGM’s ability to streamline research workflows through its comprehensive genome-wide approach and cost-effectiveness, when compared to traditional cytogenetic methods. This versatility was supported by multiple posters, such as those from Medicover Genetics and Radboud UMC, which demonstrated OGM’s effectiveness in analyzing complex regions and detecting SVs that were missed by other methods. Jasmin Maier (Medicover Genetics) investigated the complex PMS2 region, crucial for conditions like Lynch syndrome, and found OGM revealed clinically relevant SVs that were previously undetected. Radboud UMC’s research, led by Dr. Suzanne de Bruijn, showed that OGM detected a second variant in ICQB1– an insertion- in a case of Senior-Loken syndrome, a rare inherited disorder, highlighting OGM’s ability to identify SVs where other technologies fall short.  

OGM: Moving Rare Disease Research Forward  

The insights shared at ESHG 2024 underscore the critical role of SVs in rare diseases and the transformative potential of OGM to uncover these elusive genetic changes. By offering unparalleled sensitivity and specificity in SV detection, OGM can address a significant gap in current analytical capabilities.  

As Bionano continues to advance the OGM workflow, the future of genetic research looks promising. OGM’s ability to uncover the genetic basis of rare conditions may lead to new therapeutic approaches and improved research outcomes.