View Only-Clinical Utility of Mate Pair Sequencing-Clinical Utility of Mate Pair Sequencing

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Video Summary
Welcome to the ACMG Genomics Case Conference. This is a monthly series planned by the ACMG Education Committee. The conference aims to provide educational content for laboratories that perform genome-scale testing and the clinicians involved in the cases. Today's event focuses on discussing the clinical utility of mate pair sequencing. The presenters, Elise Mitchell and Dr. Nicole Hottman, are from the Genomics Laboratory at Mayo Clinic. They have disclosed no conflicts of interest. The conference is approved for one CME credit. Attendees who registered for the credit will receive an email with an evaluation and questions after the event. The specific learning objectives for today's conference are to discuss the limitations of cytogenetic testing, describe how mate pair sequencing works and its differences from other whole-genome sequencing technologies, and identify situations where mate pair sequencing may be beneficial. Throughout the conference, attendees can ask questions using the Q&A box. The presenters will answer them at the end of the presentation. Mate pair sequencing is a specialized library preparation technique followed by whole-genome paired-end sequencing. It uses large input DNA fragments of about 3-5 kb, with the advantage of detecting structural variations at lower sequencing depths. The process involves circularizing the fragments, fragmenting them again, capturing them, and performing paired-end sequencing. The resulting reads are mapped to the genome, allowing the identification of breakpoints and gene disruptions. Mate pair sequencing offers clinical insights into various cases. For example, in a prenatal case with a fetus presenting with a structural brain malformation, mate pair sequencing revealed a balanced rearrangement involving chromosomes 1 and 9. Further analysis showed that the rearrangement disrupted the AKT3 gene, which is associated with the Omegalencephaly Polymicrogeria Polydactyly Hydrocephaly Syndrome 2. This understanding could have led to better-informed pregnancy decisions if the assay was available earlier. Mate pair sequencing is also useful in determining the orientation and genomic location of duplications. In a case of a female patient with developmental and speech delay, mate pair sequencing revealed that a duplication on the X chromosome did not disrupt the BRWD3 gene, but rather inserted downstream of it. This information helped clarify the clinical significance of the duplication and potential treatment options. Additionally, mate pair sequencing has shown promise in detecting balanced chromosome rearrangements in oncology cases. In a case of a patient with B-cell acute lymphoblastic leukemia, mate pair sequencing revealed a translocation between chromosomes 12 and 15, resulting in a fusion gene involving the ETB6 and NTRK3 genes. This fusion gene could be targeted with tyrosine kinase inhibitors, providing potential therapeutic options. Overall, mate pair sequencing offers valuable insights into complex rearrangements and expands diagnostic capabilities. The technology is not validated for FFPE specimens, but the versatility of mate pair sequencing allows for exploration in different sample types.
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Presented by Mayo Clinic
Keywords
ACMG Genomics Case Conference
mate pair sequencing
clinical utility
whole-genome sequencing
structural variations
gene disruptions
prenatal case
balanced rearrangement
fusion gene