#419 Optical Genome Mapping and Long-Read Sequencing: Unlocking Rare Diagnoses

What happens when traditional genetic testing leaves patients and families without answers? Emerging technologies like optical genome mapping (OGM) and long-read sequencing are expanding what laboratories can detect, from complex structural variants to difficult-to-analyze repetitive regions of the genome. These advances are already changing clinical testing strategies and helping uncover diagnoses that previously remained out of reach.

In this episode, we welcome back Dr. Nikhil Sahajpal, Assistant Laboratory Director at Greenwood Genetic Center (GGC), who previously joined us in Episode 362 to introduce optical genome mapping. Now, nearly two years after GGC began offering OGM clinically, Dr. Sahajpal shares how the technology is being integrated into rare disease diagnostics, including additional diagnostic findings in at least 5% of previously unsolved cases.

The conversation takes a closer look at facioscapulohumeral muscular dystrophy (FSHD), a genetically complex condition involving D4Z4 repeat contractions, epigenetic changes, and inappropriate DUX4 expression. Dr. Sahajpal explains how OGM and short-read sequencing can work together to distinguish FSHD1 from FSHD2, and why the laboratory is evaluating long-read sequencing as a potential way to streamline this testing.

We also explore targeted applications of OGM and long-read sequencing, including clarifying DMD duplications, mapping structural variant breakpoints, and determining whether variants are in cis or trans. Finally, Dr. Sahajpal discusses where long-read genome sequencing fits into the rare disease diagnostic workflow and whether a more comprehensive, unified genetic test could eventually reduce the need for multiple testing platforms.

Episode Discussion Topics

• How optical genome mapping compares with karyotyping, FISH, and chromosomal microarray
• Greenwood Genetic Center's clinical experience with OGM and its additional diagnostic yield in previously unsolved rare disease cases
• When OGM may serve as a reflex test following negative genome sequencing
• The genetics of FSHD1, including D4Z4 repeat contractions, permissive haplotypes, and DUX4 expression
• Why chromosome 4 and chromosome 10 repeat regions complicate FSHD testing
• How OGM and short-read sequencing contribute to distinguishing FSHD1 and FSHD2
• The potential for long-read sequencing to assess repeat size, sequence variants, and DNA methylation
• When long-read genome sequencing may be appropriate for patients with broad or nonspecific phenotypes
• How targeted OGM can clarify DMD duplications and change carrier screening interpretation
• Using targeted long-read sequencing to phase variants in recessive conditions without parental samples
• The limitations of phenotype-driven variant analysis and the future of comprehensive genomic testing

Resources & Links

• Greenwood Genetic Center
  • OGM Complete
  • OGM Targeted 
  • Facioscapulohumeral Muscular Dystrophy Type 2 (FSHD2) NGS Panel
  • FSHD1
  • Long-read Sequencing-Trio Analysis 
  • Long-read Sequencing-Targeted Analysis
• Sahajpal Completes Laboratory Fellowship at GGC and Joins Faculty
• Sahajpal NS, Mondal AK, Singh H, Vashisht A, Ananth S, Saul D, Hastie AR, Hilton B, DuPont BR, Savage NM, Kota V, Chaubey A, Cortes JE, Kolhe R. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers. Cancers (Basel). 2023 Jun 16;15(12):3214. doi: 10.3390/cancers15123214. PMID: 37370824; PMCID: PMC10296552.

Relevant DNA Today Podcast Episode

• #362 Optical Genome Mapping: Detecting Structural Variants Missed by Traditional Tests (with guest Dr. Nikhil Sahajpal)
• #279 Reflecting on 50 Years of Greenwood Genetic Center
• #183 Dr. Miga and Dr. Phillippy on the Telomere to Telomere Consortium
• #182 Eric Green on the Complete Human Genome Project 
• #145 Greenwood Genetic Center on Epigenetics

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